Certain chemical entities, compositions, and methods

ABSTRACT

Chemical entities that are quinoxaline kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

CROSS-REFERENCE

This application is a continuation of U.S. Utility application Ser. No.15/489,679, filed Apr. 17, 2017, now U.S. Pat. No. 9,908,866, which is acontinuation of U.S. Utility application Ser. No. 14/374,216, filed Nov.6, 2014, now U.S. Pat. No. 9,670,180, which is a national stage entry ofPCT/US2013/023313, filed Jan. 25, 2013, which claims benefit of U.S.Provisional Applications 61/590,719 and 61/590,744, both filed Jan. 25,2012, each of which is incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

There are at least 400 enzymes identified as protein kinases. Theseenzymes catalyze the phosphorylation of target protein substrates. Thephosphorylation is usually a transfer reaction of a phosphate group fromATP to the protein substrate. The specific structure in the targetsubstrate to which the phosphate is transferred is a tyrosine, serine orthreonine residue. Since these amino acid residues are the targetstructures for the phosphoryl transfer, these protein kinase enzymes arecommonly referred to as tyrosine kinases or serine/threonine kinases.

The phosphorylation reactions, and counteracting phosphatase reactions,at the tyrosine, serine and threonine residues are involved in countlesscellular processes that underlie responses to diverse intracellularsignals (typically mediated through cellular receptors), regulation ofcellular functions, and activation or deactivation of cellularprocesses. A cascade of protein kinases often participate inintracellular signal transduction and are necessary for the realizationof these cellular processes. Because of their ubiquity in theseprocesses, the protein kinases can be found as an integral part of theplasma membrane or as cytoplasmic enzymes or localized in the nucleus,often as components of enzyme complexes. In many instances, theseprotein kinases are an essential element of enzyme and structuralprotein complexes that determine where and when a cellular processoccurs within a cell.

The identification of effective small compounds which specificallyinhibit signal transduction and cellular proliferation by modulating theactivity of tyrosine and serine/threonine kinases to regulate andmodulate abnormal or inappropriate cell proliferation, differentiation,or metabolism is therefore desirable. In particular, the identificationof compounds that specifically inhibit the function of a kinase which isessential for processes leading to cancer would be beneficial.

SUMMARY OF THE INVENTION

In one aspect, provided is a compound of Formula I

or Formula II

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,sulfonyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted heterocycloalkyloxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted aryloxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, optionally substituted amino, optionallysubstituted acyl, optionally substituted alkoxycarbonyl, optionallysubstituted aminocarbonyl, optionally substituted aminosulfonyl,optionally substituted carbamimidoyl, or optionally substituted alkynyl;

R₉ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and R₁₁ ishydroxyl, formyl, optionally substituted alkoxy, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃, where R₁₂ is optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R₁₃ and R₁₄ are independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; or R₁₂ and R₁₃ may be joined togetherwith any intervening atoms to form an optionally substitutedheterocycloalkyl ring;

or R₉ and R₁₁ may be joined together with any intervening atoms to forman optionally substituted heterocycloalkyl ring.

With respect to any one of the above-mentioned aspects, described beloware some specific embodiments.

In some embodiments, R₁ is hydrogen, cyano, optionally substitutedalkoxy, optionally substituted aryloxy, optionally substituted amino,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl. Insome embodiments, R₁ is hydrogen, cyano, optionally substituted alkoxy,optionally substituted amino, or optionally substituted lower alkyl. Insome embodiments, R₁ is optionally substituted aryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl. Insome embodiments, R₁ is optionally substituted morpholinyl,pyrrolidinyl, optionally substituted piperazinyl, optionally substitutedpyrrolidinyl, optionally substituted piperidinyl, optionally substitutedimidazolyl, optionally substituted pyrazolyl, or optionally substitutedpyridyl.

In some embodiments, R₂, R₃, R₄, and R₅ are independently hydrogen,halo, optionally substituted alkoxy, or optionally substituted alkyl. Inone embodiment, R₂, R₃, R₄, and R₅ are hydrogen.

In some cases, each of R₆, R₇, R₈, and R₁₀ is independently hydrogen,cyano, halo, optionally substituted alkoxy, optionally substitutedalkyl, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, or optionallysubstituted aminosulfonyl. In some embodiments, R₆ is halo. In a furtherembodiment, R₆ is fluoro. In some other embodiments, R₇ is halo. In afurther embodiment, R₇ is fluoro. In some other embodiments, R₆ is haloand R₈ is hydrogen. In a further embodiment, R₆ is fluoro and R₈ ishydrogen. In some other embodiments, R₇ is halo and R₈ is hydrogen. In afurther embodiment, R₇ is fluoro and R₈ is hydrogen. In some otherembodiments, each of R₆ and R₇ is halo. In a further embodiment, each ofR₆ and R₇ is fluoro. In a still further embodiment, R₈ is hydrogen.

In some embodiments, R₉ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₉ is hydrogen.

In some embodiments, R₁₁ is optionally substituted alkyl, —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃. In someembodiments, R₁₁ is —COR₁₂, CO₂R₁₂ or —CONR₁₂R₁₃. In some embodiments,R₁₁ is —COR₁₂. In some embodiments, R₁₁ is —CONR₁₂R₁₃.

In some embodiments, R₁₂ is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, R₁₂ is lower alkyl, aryl optionally substituted withone or two groups independently chosen from halo, cyano, lower alkyl,amino, lower alkoxy, heteroaryl optionally substituted with one or twogroups independently chosen from halo, cyano, lower alkyl, amino, orlower alkoxy.

In some embodiments, R₁₃ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₁₃ is hydrogen.

In some embodiments, R₁₂ and R₁₃ are joined together with anyintervening atoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₁₂ and R₁₃ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, and1-4,-diazocan-1-yl, each of which is optionally substituted with one ortwo groups independently chosen from hydroxyl, amino, oxo, and loweralkyl optionally substituted with hydroxy.

In some embodiments, R₁₄ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₁₄ is hydrogen.

In some embodiments, R₉ and R₁₁ are joined together with any interveningatoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₉ and R₁₁ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, and1-4,-diazocan-1-yl, each of which is optionally substituted with one ortwo groups independently chosen from hydroxyl, amino, oxo, and loweralkyl optionally substituted with hydroxy.

In some embodiments, each of R₆ and R₇ is independently halo orhydrogen, and R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃, and wherein R₁₂ is optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R₁₃ and R₁₄ are independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl, oroptionally substituted heterocycloalkyl. In a further embodiment, eachof R₆ and R₇ is independently fluoro or hydrogen. In a furtherembodiment, R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃. In yet a further embodiment, R₉ is hydrogen or optionallysubstituted lower alkyl.

In some cases, each of R₆ and R₇ is independently halo or hydrogen, andR₁₁ is —COR₁₂, —CO₂R₁₂, or —CONR₁₂R₁₃. In some embodiment, each of R₆and R₇ is independently fluoro or hydrogen. In a further embodiment, R₁is hydrogen, cyano, optionally substituted alkoxy, optionallysubstituted amino, or optionally substituted lower alkyl, optionallysubstituted morpholinyl, optionally substituted piperazinyl, optionallysubstituted pyrrolidinyl, optionally substituted piperidinyl, optionallysubstituted imidazolyl, optionally substituted pyrazolyl, or optionallysubstituted pyridyl. In a yet further embodiment, R₉ is hydrogen oroptionally substituted lower alkyl. In a still further embodiment, R₈ ishydrogen. In a yet still further embodiment, R₁₁ is —COR₁₂, —CO₂R₁₂,—CONR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃.

In some cases, R₇ and R₈ are hydrogen, In some embodiments, each of R₆and R₁₀ is independently halo. In a further embodiment, R₆ is fluoro. Ina further embodiment, R₁₀ is fluoro. a further In a still furtherembodiment, R₁ is hydrogen, cyano, optionally substituted alkoxy,optionally substituted amino, optionally substituted lower alkyl,optionally substituted morpholinyl, optionally substituted piperazinyl,optionally substituted pyrrolidinyl, optionally substituted piperidinyl,optionally substituted imidazolyl, optionally substituted pyrazolyl, oroptionally substituted pyridyl. In a yet still further embodiment, R₂,R₃, R₄, and R₅ are hydrogen. In another yet still further embodiment, R₉is hydrogen and R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound or pharmaceutically acceptable salt of any one of compoundsdescribed herein. The pharmaceutical composition may be formulated in aform which is a tablet, capsule, powder, liquid, suspension,suppository, or aerosol. The pharmaceutical composition may be packagedwith instructions for using the composition to treat a subject sufferingfrom cancer.

In another aspect, the present disclosure provides a method of treatingcancer in a subject which comprises administering to a subject in needthereof a therapeutically effective amount of a compound orpharmaceutically acceptable salt of any one of the compounds describedherein. The cancer may be colon carcinoma, pancreatic cancer, breastcancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma,angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, non-small cell lungcancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocyticleukemia and acute myelocytic leukemia (myeloblastic, promyelocytic,myelomonocytic, monocytic and erythroleukemia); chronic leukemia(chronic myelocytic (granulocytic) leukemia and chronic lymphocyticleukemia); and polycythemia vera, lymphoma (Hodgkin's disease andnon-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, or heavy chain disease. In a further embodiment, thecancer is melanoma, non-small cell lung cancer, thyroid cancer, ovariancancer, or colon cancer. The melanoma may be unresectable or metastaticmelanoma.

In another aspect, the present disclosure provides a method of treatinga disorder mediated by Raf in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound or pharmaceutically acceptable salt of any one of the compoundsdescribed herein.

In another aspect, the present disclosure provides a method of treatinga disorder in a subject in need thereof, comprising: a) determining thepresence or absence of a B-Raf (BRAF) mutation in a biological sampleisolated from the subject; and b) if a BRAF mutation is determined to bepresent in the subject, administering to the subject a therapeuticallyeffective amount of a compound or pharmaceutically acceptable salt ofany one of the compounds described herein.

The BRAF mutation may be V600E or may be in codon 600. In someembodiments, determining the presence of absence of the BRAF mutationcomprises amplifying B-raf nucleic acid from the biological sample andsequencing the amplified nucleic acid. In some other embodiments,determining the presence of absence of the BRAF mutation comprisesdetecting a mutant B-raf polypeptide in the biological sample using abinding agent to a mutant B-raf polypeptide. The binding agent may be anantibody. The biological sample may be isolated from a tumor of thesubject.

In another aspect, the present disclosure provides a method of treatinga disorder mediated by KDR in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound or pharmaceutically acceptable salt of any one of the compoundsdescribed herein.

In some embodiments, the disorder is cancer. The cancer may be coloncarcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostatecancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms' tumor, cervical cancer, testicular tumor, lungcarcinoma, small cell lung carcinoma, non-small cell lung cancer,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma,melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocyticleukemia and acute myelocytic leukemia (myeloblastic, promyelocytic,myelomonocytic, monocytic and erythroleukemia); chronic leukemia(chronic myelocytic (granulocytic) leukemia and chronic lymphocyticleukemia); and polycythemia vera, lymphoma (Hodgkin's disease andnon-Hodgkin's disease), multiple myeloma, Waldenstrom'smacroglobulinemia, or heavy chain disease. In a further embodiment, thecancer is melanoma, non-small cell lung cancer, thyroid cancer, ovariancancer, or colon cancer. The melanoma may be unresectable or metastaticmelanoma.

The treatment method described herein may further comprise administeringan additional anti-cancer and/or cytotoxic agent.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference in their entiretiesto the same extent as if each individual publication, patent, or patentapplication was specifically and individually indicated to beincorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following words and phrases are generally intendedto have the meanings as set forth below, except to the extent that thecontext in which they are used indicates otherwise.

The following abbreviations and terms have the indicated meaningsthroughout:

-   AcOH=acetic acid-   Boc=tert-butoxycarbonyl-   c-=cyclo-   DCC=dicyclohexylcarbodiimide-   DIEA=N,N-diisopropylethylamine-   DMAP=4-dimethylaminopyridine-   DMF=N,N-dimethylformamide-   DMSO=dimethyl sulfoxide-   EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-   eq=equivalent(s)-   Et=ethyl-   EtOAc or EA=ethyl acetate-   EtOH=ethanol-   g=gram-   h or hr=hour-   HBTU=O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt=hydroxybenzotriazole-   HPLC=high pressure liquid chromatography-   i-=iso-   kg or Kg=kilogram-   L or 1=liter-   LC/MS=LCMS=liquid chromatography-mass spectrometry-   LRMS=low resolution mass spectrometry-   m/z=mass-to-charge ratio-   Me=methyl-   MeOH=methanol-   mg=milligram-   min=minute-   mL=milliliter-   mmol=millimole-   n-=normal-   NaOAc=sodium acetate-   PE=petroleum ether-   Ph=phenyl-   Prep=preparative-   quant.=quantitative-   RP-HPLC=reverse phase-high pressure liquid chromatography-   rt or RT=room temperature-   s-=sec-=secondary-   t-=tert-=tertiary-   THF=tetrahydrofuran-   TLC=thin layer chromatography-   UV=ultraviolet

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence.

As used herein, a dash (“-”) that is not between two letters or symbolsis used to indicate a point of attachment for a substituent. Forexample, —CONH₂ is attached through the carbon atom.

As used herein, “optional” or “optionally” is meant that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances wherein the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted alkyl” encompasses both “alkyl” and “substitutedalkyl” as defined below. It will be understood by those skilled in theart, with respect to any group containing one or more substituents, thatsuch groups are not intended to introduce any substitution orsubstitution patterns that are sterically impractical, syntheticallynon-feasible and/or inherently unstable.

As used herein, “alkyl” refers to straight chain and branched chainhaving the indicated number of carbon atoms, usually from 1 to 20 carbonatoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. Forexample C₁-C₆ alkyl encompasses both straight and branched chain alkylof from 1 to 6 carbon atoms. When an alkyl residue having a specificnumber of carbons is named, all branched and straight chain versionshaving that number of carbons are intended to be encompassed; thus, forexample, “butyl” is meant to include n-butyl, sec-butyl, isobutyl andt-butyl; “propyl” includes n-propyl and isopropyl. “Lower alkyl” refersto alkyl groups having one to six carbons. Examples of alkyl groupsinclude methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, 3-methylpentyl, and the like. Alkylene is a subset of alkyl,referring to the same residues as alkyl, but having two points ofattachment. Alkylene groups will usually have from 2 to 20 carbon atoms,for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. Forexample, C₀ alkylene indicates a covalent bond and C₁ alkylene is amethylene group.

As used herein, “alkenyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon double bondderived by the removal of one molecule of hydrogen from adjacent carbonatoms of the parent alkyl. The group may be in either the cis or transconfiguration about the double bond(s). Typical alkenyl groups include,but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such asbut-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl;and the like. In certain embodiments, an alkenyl group has from 2 to 20carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Loweralkenyl” refers to alkenyl groups having two to six carbons.

As used herein, “alkynyl” refers to an unsaturated branched orstraight-chain alkyl group having at least one carbon-carbon triple bondderived by the removal of two molecules of hydrogen from adjacent carbonatoms of the parent alkyl. Typical alkynyl groups include, but are notlimited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl;butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and thelike. In certain embodiments, an alkynyl group has from 2 to 20 carbonatoms and in other embodiments, from 3 to 6 carbon atoms. “Loweralkynyl” refers to alkynyl groups having two to six carbons.

As used herein, “cycloalkyl” refers to a non-aromatic carbocyclic ring,usually having from 3 to 7 ring carbon atoms. The ring may be saturatedor have one or more carbon-carbon double bonds. Examples of cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groupssuch as norbornane.

As used herein, “alkoxy” refers to an alkyl group of the indicatednumber of carbon atoms attached through an oxygen bridge such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy,tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy,hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.Alkoxy groups will usually have from 1 to 7 carbon atoms attachedthrough the oxygen bridge. “Lower alkoxy” refers to alkoxy groups havingone to six carbons.

As used herein, “acyl” refers to the groups H—C(O)—; (alkyl)-C(O)—;(cycloalkyl)-C(O)—; (aryl)-C(O)—; (heteroaryl)-C(O)—; and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein alkyl,cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as describedherein. Acyl groups have the indicated number of carbon atoms, with thecarbon of the keto group being included in the numbered carbon atoms.For example a C₂ acyl group is an acetyl group having the formulaCH₃(C═O)—.

As used herein, “formyl” refers to the group —C(O)H.

As used herein, “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker.

As used herein, “azido” refers to the group —N₃.

As used herein, “amino” refers to the group —NH₂.

As used herein, “mono- and di-(alkyl)amino” refers to secondary andtertiary alkyl amino groups, wherein the alkyl groups are as definedabove and have the indicated number of carbon atoms. The point ofattachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino, andmethyl-propyl-amino.

As used herein, “aminocarbonyl” refers to the group —CONR^(b)R^(c),where

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl,optionally substituted alkoxy; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 4- to 8-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms chosen from O, N, and S in the heterocycloalkylring;

where each substituted group is independently substituted with one ormore substituents independently chosen from C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl,—OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl,halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl),—NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄alkylphenyl), cyano, nitro, oxo (as a substituent for cycloalkyl,heterocycloalkyl, or heteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl),—NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl), —SO₂(phenyl),—SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl),—NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “aryl” refers to: 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene.

For example, aryl includes 6-membered carbocyclic aromatic rings fusedto a 4- to 8-membered heterocycloalkyl ring containing 1 or moreheteroatoms chosen from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the point of attachment may be at the carbocyclic aromatic ring or theheterocycloalkyl ring. Bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. Bivalent radicals derived from univalentpolycyclic hydrocarbon radicals whose names end in “-yl” by removal ofone hydrogen atom from the carbon atom with the free valence are namedby adding “-idene” to the name of the corresponding univalent radical,e.g. a naphthyl group with two points of attachment is termednaphthylidene. Aryl, however, does not encompass or overlap in any waywith heteroaryl, separately defined below. Hence, if one or morecarbocyclic aromatic rings is fused with a heterocycloalkyl aromaticring, the resulting ring system is heteroaryl, not aryl, as definedherein.

As used herein, “aryloxy” refers to the group —O-aryl.

As used herein, “aralkyl” refers to the group -alkyl-aryl.

As used herein, “carbamimidoyl” refers to the group —C(═NH)—NH2.

As used herein, “substituted carbamimidoyl” refers to the group—C(═NR^(e))—NR^(f)R^(g) where

R^(e) is chosen from hydrogen, cyano, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocycloalkyl; and

R^(f) and R^(g) are independently chosen from hydrogen optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl,

provided that at least one of R^(e), R^(f), and R^(g) is not hydrogenand wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl, heterocycloalkyl, and heteroaryl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C1-C6 alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C1-C6 alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C1-C4 alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl, heterocycloalkyl, orheteroaryl), —CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl),—N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl),—C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄alkyl, —SO2(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂ NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “halo” refers to fluoro, chloro, bromo, and iodo, andthe term “halogen” includes fluorine, chlorine, bromine, and iodine.

As used herein, “haloalkyl” refers to alkyl as defined above having thespecified number of carbon atoms, substituted with 1 or more halogenatoms, up to the maximum allowable number of halogen atoms. Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

As used herein, “heteroaryl” refers to:

5- to 7-membered aromatic, monocyclic rings containing one or more, forexample, from 1 to 4, or in certain embodiments, from 1 to 3,heteroatoms chosen from N, O, and S, with the remaining ring atoms beingcarbon;

bicyclic heterocycloalkyl rings containing one or more, for example,from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring; and

tricyclic heterocycloalkyl rings containing one or more, for example,from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms chosenfrom N, O, and S, with the remaining ring atoms being carbon and whereinat least one heteroatom is present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered heterocycloalkyl,aromatic ring fused to a 4- to 8-membered cycloalkyl or heterocycloalkylring. For such fused, bicyclic heteroaryl ring systems wherein only oneof the rings contains one or more heteroatoms, the point of attachmentmay be at either ring. When the total number of S and O atoms in theheteroaryl group exceeds 1, those heteroatoms are not adjacent to oneanother. In certain embodiments, the total number of S and O atoms inthe heteroaryl group is not more than 2. In certain embodiments, thetotal number of S and O atoms in the aromatic heterocycle is not morethan 1. Examples of heteroaryl groups include, but are not limited to,(as numbered from the linkage position assigned priority 1), 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl,triazolyl, quinolinyl, quinoxalinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinolinyl. Bivalent radicals derived fromunivalent heteroaryl radicals whose names end in “-yl” by removal of onehydrogen atom from the atom with the free valence are named by adding“-idene” to the name of the corresponding univalent radical, e.g. apyridyl group with two points of attachment is a pyridylidene.Heteroaryl does not encompass or overlap with aryl, cycloalkyl, orheterocycloalkyl, as defined herein.

Substituted heteroaryl also includes ring systems substituted with oneor more oxide (—O⁻) substituents, such as pyridinyl N-oxides.

As used herein, “heterocycloalkyl” refers to a single, non-aromaticring, usually with 3 to 8 ring atoms, containing at least 2 carbon atomsin addition to 1-3 heteroatoms independently chosen from oxygen, sulfur,and nitrogen, as well as combinations comprising at least one of theforegoing heteroatoms. The ring may be saturated or have one or morecarbon-carbon double bonds. Suitable heterocycloalkyl groups include,for example (as numbered from the linkage position assigned priority 1),2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl,3-piperidyl, 4-piperidyl, 2,5-piperazinyl, pyrrolidinyl, azetidinyl,pyranyl, 2,3-dihydrofuranyl, or 2,5-dihydrofuranyl. Morpholinyl groupsare also contemplated, including 2-morpholinyl and 3-morpholinyl(numbered wherein the oxygen is assigned priority 1). Substitutedheterocycloalkyl also includes ring systems substituted with one or moreoxo (═O) or oxide (—O⁻) substituents, such as piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl.

“Heterocycloalkyl” also includes bicyclic ring systems wherein onenon-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2carbon atoms in addition to 1-3 heteroatoms independently chosen fromoxygen, sulfur, and nitrogen, as well as combinations comprising atleast one of the foregoing heteroatoms; and the other ring, usually with3 to 7 ring atoms, optionally contains 1-3 heteratoms independentlychosen from oxygen, sulfur, and nitrogen and is not aromatic.

As used herein, “sulfanyl” refers to the groups: —S-(optionallysubstituted (C₁-C₆)alkyl), —S-(optionally substituted cycloalkyl),—S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl), and —S-(optionally substituted heterocycloalkyl). Hence,sulfanyl includes the group C₁-C₆ alkylsulfanyl.

As used herein, “sulfinyl” refers to the groups: —S(O)-(optionallysubstituted (C₁-C₆)alkyl), —S(O)-(optionally substituted cycloalkyl),—S(O)-(optionally substituted aryl), —S(O)-optionally substitutedheteroaryl), —S(O)-(optionally substituted heterocycloalkyl); and—S(O)-(optionally substituted amino).

As used herein, “sulfonyl” refers to the groups: —S(O₂)-(optionallysubstituted (C₁-C₆)alkyl), —S(O₂)-(optionally substituted cycloalkyl),—S(O₂)-(optionally substituted aryl), —S(O₂)-(optionally substitutedheteroaryl), —S(O₂)-(optionally substituted heterocycloalkyl), and—S(O₂)-(optionally substituted amino).

As used herein, “substituted” refers to any one or more hydrogens on thedesignated atom or group is replaced with a selection from the indicatedgroup, provided that the designated atom's normal valence is notexceeded. When a substituent is oxo (i.e. ═O) then 2 hydrogens on theatom are replaced. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates. A stable compound or stable structure ismeant to imply a compound that is sufficiently robust to surviveisolation from a reaction mixture, and subsequent formulation as anagent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

As used herein, the terms “substituted” alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl, unless otherwise expressly defined,refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl wherein one or more (such as up to 5, for example, up to 3)hydrogen atoms are replaced by a substituent independently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, azido,nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),optionally substituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)), where

R^(a) is chosen from optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;R^(b) is chosen from hydrogen, optionally substituted C₁-C₆ alkyl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, and optionallysubstituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, for example, upto 3) hydrogen atoms are replaced by a substituent independently chosenfrom

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e. —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a)), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

In some embodiments, a substituted alkoxy group is “polyalkoxy” or—O-(optionally substituted alkylene)-(optionally substituted alkoxy),and includes groups such as —OCH₂CH₂OCH₃, and residues of glycol etherssuch as polyethyleneglycol, and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of 2-20, such as 2-10, and for example, 2-5. Another substitutedalkoxy group is hydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is an integerof 1-10, such as 1-4.

As used herein, “substituted alkoxycarbonyl” refers to the group(substituted alkyl)-O—C(O)— wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedrefers to alkyl wherein one or more (such as up to 5, for example, up to3) hydrogen atoms are replaced by a substituent independently chosenfrom

—R^(a), —OR^(b), optionally substituted amino (including —NR^(c)COR^(b),—NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c), —NR^(b)C(NR^(c))NR^(b)R^(c),—NR^(b)C(NCN)NR^(b)R^(c), and —NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo(as a substituent for cycloalkyl or heterocycloalkyl), optionallysubstituted acyl (such as —COR^(b)), optionally substitutedalkoxycarbonyl (such as —CO₂R^(b)), aminocarbonyl (such as—CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a), —OCONR^(b)R^(c),—OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)), sulfinyl (such as—SOR^(a), and sulfonyl (such as —SO₂R^(a) and —SO₂NR^(b)R^(c)),where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl).

As used herein, “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(e) wherein R^(d) is chosen from hydroxyl, formyl, optionallysubstituted alkoxy, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted acyl, optionally substitutedcarbamimidoyl, aminocarbonyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, andwherein R^(e) is chosen from optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl, andwherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,for example, up to 3) hydrogen atoms are replaced by a substituentindependently chosen from —R^(a), —OR^(b), optionally substituted amino(including —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—NR^(b)C(NR^(c))NR^(b)R^(c), —NR^(b)C(NCN)NR^(b)R^(c), and—NR^(c)SO₂R^(a)), halo, cyano, nitro, oxo (as a substituent forcycloalkyl or heterocycloalkyl), optionally substituted acyl (such as—COR^(b)), optionally substituted alkoxycarbonyl (such as —CO₂R^(b)),aminocarbonyl (such as —CONR^(b)R^(c)), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —OP(O)(OR^(b))OR^(c), sulfanyl (such as SR^(b)),sulfinyl (such as —SOR^(a), and sulfonyl (such as —SO₂R^(a) and—SO₂NR^(b)R^(c)),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently chosen from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substituent for cycloalkyl or heterocycloalkyl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ alkylphenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl,—SO₂(C₁-C₄ alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂,—SO₂NH(C₁-C₄ alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl),—NHSO₂(phenyl), and —NHSO₂(C₁-C₄ haloalkyl); and

wherein optionally substituted acyl, optionally substitutedalkoxycarbonyl, sulfinyl and sulfonyl are as defined herein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d), and NR^(d)R^(d) each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds described herein include, but are not limited to, theiroptical isomers, racemates, and other mixtures thereof. In thosesituations, the single enantiomers or diastereomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolutionof the racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column. In addition,compounds include Z- and E-forms (or cis- and trans-forms) of compoundswith carbon-carbon double bonds. Where compounds described herein existin various tautomeric forms, the term “compound” is intended to includeall tautomeric forms of the compound.

Compounds of Formula I or II also include crystalline and amorphousforms of those compounds, including, for example, polymorphs,pseudopolymorphs, solvates (including hydrates), unsolvated polymorphs(including anhydrates), conformational polymorphs, and amorphous formsof the compounds, as well as mixtures thereof. “Crystalline form,”“polymorph,” and “novel form” may be used interchangeably herein, andare meant to include all crystalline and amorphous forms of thecompound, including, for example, polymorphs, pseudopolymorphs, solvates(including hydrates), unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto. Similarly, “pharmaceutically acceptable forms” of compounds ofFormula I or II also include crystalline and amorphous forms of thosecompounds, including, for example, polymorphs, pseudopolymorphs,solvates (including hydrates), unsolvated polymorphs (includinganhydrates), conformational polymorphs, and amorphous forms of thepharmaceutically acceptable salts, as well as mixtures thereof.

A “solvate” is formed by the interaction of a solvent and a compound.The term “compound” is intended to include solvates of compounds.Similarly, “pharmaceutically acceptable salts” includes solvates ofpharmaceutically acceptable salts. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

Compounds of Formula I or II also include other pharmaceuticallyacceptable forms of the recited compounds, including chelates,non-covalent complexes, prodrugs, and mixtures thereof.

A “chelate” is formed by the coordination of a compound to a metal ionat two (or more) points. The term “compound” is intended to includechelates of compounds. Similarly, “pharmaceutically acceptable salts”includes chelates of pharmaceutically acceptable salts.

A “non-covalent complex” is formed by the interaction of a compound andanother molecule wherein a covalent bond is not formed between thecompound and the molecule. For example, complexation can occur throughvan der Waals interactions, hydrogen bonding, and electrostaticinteractions (also called ionic bonding). Such non-covalent complexesare included in the term “compound”. Similarly, pharmaceuticallyacceptable salts include “non-covalent complexes” of pharmaceuticallyacceptable salts.

The term “hydrogen bond” refers to a form of association between anelectronegative atom (also known as a hydrogen bond acceptor) and ahydrogen atom attached to a second, relatively electronegative atom(also known as a hydrogen bond donor). Suitable hydrogen bond donor andacceptors are well understood in medicinal chemistry.

“Hydrogen bond acceptor” refers to a group comprising an oxygen ornitrogen, such as an oxygen or nitrogen that is sp²-hybridized, an etheroxygen, or the oxygen of a sulfoxide or N-oxide.

The term “hydrogen bond donor” refers to an oxygen, nitrogen, orheteroaromatic carbon that bears a hydrogen. group containing a ringnitrogen or a heteroaryl group containing a ring nitrogen.

The compounds disclosed herein can be used in different enrichedisotopic forms, e.g., enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or¹⁴C. In one particular embodiment, the compound is deuterated at atleast one position. Such deuterated forms can be made by the proceduredescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described inU.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve theefficacy and increase the duration of action of drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compoundsvia Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21;and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compounds described herein are obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

“Prodrugs” described herein include any compound that becomes a compoundof Formula I or II when administered to a subject, e.g., upon metabolicprocessing of the prodrug. Similarly, “pharmaceutically acceptablesalts” includes “prodrugs” of pharmaceutically acceptable salts.Examples of prodrugs include derivatives of functional groups, such as acarboxylic acid group, in the compounds of Formula I or II. Exemplaryprodrugs of a carboxylic acid group include, but are not limited to,carboxylic acid esters such as alkyl esters, hydroxyalkyl esters,arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugsinclude lower alkyl esters such as ethyl ester, acyloxyalkyl esters suchas pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives.

Other exemplary prodrugs include amides of carboxylic acids. Exemplaryamide prodrugs include metabolically labile amides that are formed, forexample, with an amine and a carboxylic acid. Exemplary amines includeNH₂, primary, and secondary amines such as NHR^(x), and NR^(x)R^(y),wherein R^(x) is hydrogen, (C₁-C₁₈)-alkyl, (C₃-C₇)-cycloalkyl,(C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, (C₆-C₁₄)-aryl which is unsubstitutedor substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy, fluoro, orchloro; heteroaryl-, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- where aryl isunsubstituted or substituted by a residue (C₁-C₂)-alkyl, (C₁-C₂)-alkoxy,fluoro, or chloro; or heteroaryl-(C₁-C₄)-alkyl- and in which R^(y) hasthe meanings indicated for R^(x) with the exception of hydrogen orwherein R^(x) and R_(y), together with the nitrogen to which they arebound, form an optionally substituted 4- to 7-membered heterocycloalkylring which optionally includes one or two additional heteroatoms chosenfrom nitrogen, oxygen, and sulfur. A discussion of prodrugs is providedin T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, and in Design of Prodrugs, ed. H.Bundgaard, Elsevier, 1985.

As used herein, the terms “group”, “radical” or “fragment” aresynonymous and are intended to indicate functional groups or fragmentsof molecules attachable to a bond or other fragments of molecules.

As used herein, the term “leaving group” refers to the meaningconventionally associated with it in synthetic organic chemistry, i.e.,an atom or group displaceable under nucleophilic displacementconditions. Examples of leaving groups include, but are not limited to,dimethylhydroxylamino (e.g. Weinreb amide), halogen, alkane- orarylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

As used herein, the term “protective group” or “protecting group” refersto a group which selectively blocks one reactive site in amultifunctional compound such that a chemical reaction can be carriedout selectively at another unprotected reactive site in the meaningconventionally associated with it in synthetic chemistry. Certainprocesses of this invention rely upon the protective groups to blockcertain reactive sites present in the reactants. Examples of protectinggroups can be found in Wuts et al., Green's Protective Groups in OrganicSynthesis, (J. Wiley, 4th ed. 2006).

As used herein, the term “deprotection” or “deprotecting” refers to aprocess by which a protective group is removed after a selectivereaction is completed. Certain protective groups may be preferred overothers due to their convenience or relative ease of removal. Withoutbeing limiting, deprotecting reagents for protected amino or anilinogroup include strong acid such as trifluoroacetic acid (TFA),concentrated HCl, H₂SO₄, or HBr, and the like.

As used herein, “modulation” refers to a change in activity as a director indirect response to the presence of a chemical entity as describedherein, relative to the activity of in the absence of the chemicalentity. The change may be an increase in activity or a decrease inactivity, and may be due to the direct interaction of the compound withthe a target or due to the interaction of the compound with one or moreother factors that in turn affect the target's activity. For example,the presence of the chemical entity may, for example, increase ordecrease the target activity by directly binding to the target, bycausing (directly or indirectly) another factor to increase or decreasethe target activity, or by (directly or indirectly) increasing ordecreasing the amount of target present in the cell or organism.

As used herein, “active agent” is used to indicate a chemical entitywhich has biological activity. In certain embodiments, an “active agent”is a compound having pharmaceutical utility. For example an active agentmay be an anti-cancer therapeutic.

As used herein, “significant” refers to any detectable change that isstatistically significant in a standard parametric test of statisticalsignificance such as Student's T-test, where p<0.05.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

As used herein, “therapeutically effective amount” of a chemical entitydescribed herein refers to an amount effective, when administered to ahuman or non-human subject, to provide a therapeutic benefit such asamelioration of symptoms, slowing of disease progression, or preventionof disease.

“Treating” or “treatment” encompasses administration of at least onecompound of Formula I or II, or a pharmaceutically acceptable saltthereof, to a mammalian subject, particularly a human subject, in needof such an administration and includes (i) arresting the development ofclinical symptoms of the disease, such as cancer, (ii) bringing about aregression in the clinical symptoms of the disease, such as cancer,and/or (iii) prophylactic treatment for preventing the onset of thedisease, such as cancer.

As used herein, “cancer” refers to all types of cancer or neoplasm ormalignant tumors found in mammals, including carcinomas and sarcomas.Examples of cancer are cancer of the brain, breast, cervix, colon, head& neck, kidney, lung, non-small cell lung, melanoma, mesothelioma,ovary, sarcoma, stomach, uterus and Medulloblastoma.

As used herein, “subject” refers to a mammal that has been or will bethe object of treatment, observation or experiment. The methodsdescribed herein can be useful in both human therapy and veterinaryapplications. In some embodiments, the subject is a human.

The term “mammal” is intended to have its standard meaning, andencompasses humans, dogs, cats, sheep, and cows, for example.

As used herein, the terms “BRAF”, “B-raf”, “B-Raf” and the like are usedinterchangeably to refer to the gene or protein product of the gene.

A. Compounds

In one aspect, provided is a compound of Formula I

or Formula II

or a pharmaceutically acceptable salt thereof, wherein

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl,sulfonyl, optionally substituted alkoxy, optionally substitutedcycloalkyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted heterocycloalkyloxy, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted alkenyl, optionally substituted aryloxy, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, optionally substituted amino, optionallysubstituted acyl, optionally substituted alkoxycarbonyl, optionallysubstituted aminocarbonyl, optionally substituted aminosulfonyl,optionally substituted carbamimidoyl, or optionally substituted alkynyl;

R₉ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and R₁₁ ishydroxyl, formyl, optionally substituted alkoxy, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃, where R₁₂ is optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R₁₃ and R₁₄ are independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl; or R₁₂ and R₁₃ may be joined togetherwith any intervening atoms to form an optionally substitutedheterocycloalkyl ring;

or R₉ and R₁₁ may be joined together with any intervening atoms to forman optionally substituted heterocycloalkyl ring.

With respect to any one of the two above-mentioned aspects, describedbelow are some specific embodiments.

In some embodiments, R₁ is hydrogen, cyano, halo, hydroxy, carboxy,optionally substituted alkoxy, optionally substituted aryloxy,optionally substituted alkoxycarbonyl, optionally substituted alkyl,optionally substituted aryloxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted amino, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminocarbonyl,optionally substituted aminosulfonyl, optionally substitutedcarbamimidoyl, or optionally substituted alkynyl. In a furtherembodiment, R₁ is hydrogen, cyano, optionally substituted alkoxy,optionally substituted aryloxy, optionally substituted amino, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl. In a furtherembodiment, R₁ is optionally substituted aryl, optionally substitutedheterocycloalkyl, or optionally substituted heteroaryl. In anotherembodiment, R₁ is optionally substituted morpholinyl, optionallysubstituted piperazinyl, optionally substituted pyrrolidinyl, optionallysubstituted piperidinyl, optionally substituted imidazolyl, optionallysubstituted pyrazolyl, or optionally substituted pyridyl. In otherembodiments, R₁ is chosen from pyrrolidin-1-yl, morpholin-1-yl,piperidin-1-yl, piperazin-1-yl, and 1-4,-diazocan-1-yl, each of which isoptionally substituted with one or two groups independently chosen fromhydroxyl, amino, oxo, and lower alkyl optionally substituted withhydroxy or amino. In other embodiments, R₁ is chosen from hydrogen,cyano, lower alkyl, lower alkoxy, amino, 1H-imidazol-1-yl optionallysubstituted with lower alkyl, 1H-pyrazol-4-yl optionally substitutedwith lower alkyl, 1H-pyrazol-3-yl optionally substituted with loweralkyl, pyridin-2-yl optionally substituted with lower alkyl,pyridin-3-yl optionally substituted with lower alkyl, and pyridin-4-yloptionally substituted with lower alkyl. In some embodiments, R₁ isoptionally substituted alkoxy, for example methoxy, 2-hydroxyethoxy, or2-aminoethoxy. In some embodiments, R₁ is optionally substituted loweralkyl, for example aminomethyl, dimethylaminomethyl,morpholin-1-yl-methyl, pyrrolidin-1-yl-methyl, or piperazin-1-yl-methyl.In some embodiments, R₁ is chosen from hydrogen, methyl, cyano, methoxy,aminomethyl, dimethylaminomethyl, 2-hydroxyethoxy, 2-aminoethoxy,(2-aminoethyl)amino, (2-hydroxyethyl)amino, 1H-imidazol-1-yl,2-methyl-1H-imidazol-1-yl, 5-methyl-1H-imidazol-1-yl,4-methyl-1H-imidazol-1-yl, 1H-pyrazol-4-yl, 1H-pyrazol-3-yl,pyridin-3-yl, 6-methylpyridin-3-yl, pyridin-4-yl, morpholin-1-yl,pyrrolidin-1-yl, piperazin-1-yl, morpholin-1-yl-methyl,pyrrolidin-1-yl-methyl, and piperazin-1-yl-methyl. In other embodiments,R₁ is optionally substituted heteroaryl. For example, R₁ is 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolyl, 2,4-imidazolyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiophenyl, furanyl,pyrrolyl, benzofuranyl, benzoimidazolyl, indolyl, pyridazinyl,triazolyl, quinolinyl, quinoxalinyl, pyrazolyl, or5,6,7,8-tetrahydroisoquinolinyl. In yet other embodiments, R₁ isoptionally substituted heterocycloalkyl. For example, R₁ is pyrrolidinylsuch as 2-pyrrolidinyl, imidazolidinyl such as 2,4-imidazolidinyl,pyrazolidinyl such as 2,3-pyrazolidinyl, piperidyl such as 2-piperidyl,3-piperidyl, or 4-piperidyl, piperazinyl such as 2,5-piperazinyl,pyrrolidinyl, azetidinyl, pyranyl, dihydrofuranyl such as2,3-dihydrofuranyl, or 2,5-dihydrofuranyl, morpholinyl such as2-morpholinyl or 3-morpholinyl, piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl or1,1-dioxo-1-thiomorpholinyl.

In some embodiments, each of R₂, R₃, R₄, and R₅ is independentlyhydrogen, halo, optionally substituted alkoxy, or optionally substitutedalkyl. In some embodiments, R₂ is chosen from hydrogen, halo, alkoxy,and alkyl. In some embodiments, R₂ is hydrogen.

In some embodiments, R₃ is hydrogen, halo, alkoxy, or alkyl. In someembodiments, R₃ is hydrogen. In some embodiments, R₄ is hydrogen, halo,alkoxy, or alkyl. In some embodiments, R₄ is hydrogen. In someembodiments, R₅ is hydrogen, halo, alkoxy, or alkyl. In someembodiments, R₅ is hydrogen.

In some embodiments, R₂, R₃, R₄, and R₅ are hydrogen.

In some embodiments, each of R₆, R₇, R₈, and R₁₀ is independentlyhydrogen, cyano, halo, optionally substituted alkoxy, optionallysubstituted alkyl, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted aminocarbonyl, or optionallysubstituted aminosulfonyl. In a further embodiment, each of R₆, R₇, R₈,and R₁₀ is independently hydrogen, cyano, or halo. In anotherembodiment, R₇ is halo. In yet another embodiment, R₇ is fluoro. In afurther embodiment, R₇ and R₈ are hydrogen.

In some embodiments, R₆ is hydrogen, cyano, or halo. In someembodiments, R₆ is halo. In some embodiments, R₆ is fluoro. In someembodiments, R₈ is hydrogen, cyano, or halo. In some embodiments, R₈ ishydrogen. In some embodiments, R₁₀ is hydrogen, cyano, or halo. In someembodiments, R₁₀ is hydrogen, fluoro or chloro. In some embodiments, R₇is hydrogen, cyano, or halo. In some embodiments, R₇ is hydrogen orhalo. In some embodiments, R₇ is hydrogen or fluoro. In someembodiments, R₇ is halo. In some embodiments, R₇ is fluoro.

In some embodiments, R₆ and R₇ are fluoro. For example, R₆ and R₇ arefluoro and R₁₀ is hydrogen. In other embodiments, R₆, R₇ and R₁₀ arefluoro. In some embodiments, R₆ and R₁₀ are fluoro. For example, R₆ isfluoro, R₁₀ is fluoro and R₇ is hydrogen.

In some embodiments, R₉ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₉ is hydrogen.

In some embodiments, R₁₁ is optionally substituted alkyl, —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃. In someembodiments, R₁₁ is —COR₁₂ or —CONR₁₂R₁₃. In some embodiments, R₁₁ is—COR₁₂. In some embodiments, R₁₁ is —CONR₁₂R₁₃.

In some embodiments, R₁₂ is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. Insome embodiments, R₁₂ is lower alkyl, aryl optionally substituted withone or two groups independently chosen from halo, cyano, lower alkyl,amino, and lower alkoxy, or heteroaryl optionally substituted with oneor two groups independently chosen from halo, cyano, lower alkyl, amino,and lower alkoxy. In some embodiments, R₁₂ is propyl, phenyl, pyridyl,5-fluoropyridin-3-yl, 5-chloropyridin-3-yl,2-(trifluoroethyl)pyridin-4-yl, 3-fluorophenyl, 3-chlorophenyl,4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-methoxyphenyl,4-trifluromethyl-phenyl, 3,4-di-fluoro-phenyl, 3,4-di-dichloro-phenyl,3,5-di-fluoro-phenyl, 3-chloro-4-fluoro-phenyl,4-chloro-3-fluoro-phenyl, 3-fluoro-4-trifluromethyl-phenyl,4-fluoro-3-trifluromethyl-phenyl, 4-cyano-3-fluoro-phenyl,3-chloro-4-cyano-phenyl, 4-cyano-3-trifluromethyl-phenyl3-chloro-4-trifluromethyl-phenyl, or 4-chloro-3-trifluromethyl-phenyl.

In some embodiments, R₁₃ is hydrogen or optionally substituted loweralkyl. In some embodiments, R₁₃ is hydrogen.

In some embodiments, R₁₂ and R₁₃ are joined together with anyintervening atoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₁₂ and R₁₃ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, and1-4,-diazocan-1-yl, each of which is optionally substituted with one ortwo groups independently chosen from hydroxyl, amino, oxo, and loweralkyl optionally substituted with hydroxy or amino.

In some embodiments, R₁₄ is chosen from hydrogen and optionallysubstituted lower alkyl. In some embodiments, R₁₄ is hydrogen.

In some embodiments, R₉ and R₁₁ are joined together with any interveningatoms to form an optionally substituted 4- to 8-memberedheterocycloalkyl ring. In some embodiments, R₉ and R₁₁ are joinedtogether to form a 4- to 8-membered heterocycloalkyl ring chosen frompyrrolidin-1-yl, morpholin-1-yl, piperidin-1-yl, piperazin-1-yl, and1-4,-diazocan-1-yl, each of which is optionally substituted with one ortwo groups independently chosen from hydroxyl, amino, oxo, and loweralkyl optionally substituted with hydroxy.

In some embodiments, R₆, R₇, R₈, and R₁₀ are independently hydrogen,cyano, or halo. In one embodiment, each of R₆ and R₁₀ is independentlyhalo. In a further embodiment, R₆ is halo. In a further embodiment, R₇is halo. In a further embodiment, R₈ is hydrogen.

In some embodiments, each of R₆, R₇, and R₁₀ is halo and R₁₁ is —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃, and wherein R₁₂ is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl; andR₁₃ and R₁₄ are independently hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl or optionally substitutedheterocycloalkyl. In a further embodiment, each of R₆, R₇, and R₁₀ isfluoro. In a further embodiment, R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃,—SO₂NR₁₂, or —SO₂NR₁₂R₁₃. In yet a further embodiment, R₉ is hydrogen oroptionally substituted lower alkyl.

In some embodiments, each of R₆, R₇, and R₁₀ is fluoro and R₁₁ is—COR₁₂, —CO₂R₁₂, or —CONR₁₂R₁₃. In a further embodiment, R₁ isoptionally substituted morpholinyl, optionally substituted piperazinyl,optionally substituted pyrrolidinyl, optionally substituted piperidinyl,optionally substituted imidazolyl, optionally substituted pyrazolyl, oroptionally substituted pyridyl. In a yet further embodiment, R₉ ishydrogen or optionally substituted lower alkyl.

In some embodiments, each of R₆ and R₇ is independently halo orhydrogen, and R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃,—C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃, and wherein R₁₂ is optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R₁₃ and R₁₄ are independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl, oroptionally substituted heterocycloalkyl. In a further embodiment, eachof R₆ and R₇ is independently fluoro or hydrogen. In a furtherembodiment, R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃. In yet a further embodiment, R₉ is hydrogen or optionallysubstituted lower alkyl.

In some cases, each of R₆ and R₇ is independently halo or hydrogen, andR₁₁ is —COR₁₂, —CO₂R₁₂, or —CONR₁₂R₁₃. In some embodiments, each of R₆and R₇ is independently fluoro or hydrogen. In a further embodiment, R₁is optionally substituted morpholinyl, optionally substitutedpiperazinyl, optionally substituted pyrrolidinyl, optionally substitutedpiperidinyl, optionally substituted imidazolyl, optionally substitutedpyrazolyl, or optionally substituted pyridyl. In a yet furtherembodiment, R₉ is hydrogen or optionally substituted lower alkyl. In astill further embodiment, R₈ is hydrogen. In a yet still furtherembodiment, R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃.

In another aspect, the present disclosure provides a compound orpharmaceutically acceptable salt chosen from the group consisting of:

-   1-(3-chlorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-cyanoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-((2-methoxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-((3-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chlorophenyl)-3-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(2-chloro-4,5-difluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2-chloro-4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(2,4,5-trifluoro-3-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2-chloro-4,5-difluoro-3-((3)-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2-chloro-4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,4,5-trifluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2,4,5-trifluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(2,4,5-trifluoro-3-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-4,5-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-4,5-difluorophenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluoro-5-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluoro-5-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)-4,5-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluoro-5-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluoro-5-((3-((2-methoxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,4-difluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluoro-5-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-4,5-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluoro-5-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-5-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-5-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-5-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-5-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)-5-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-5-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-5-((3-((2-methoxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-5-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-5-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-5-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chlorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluoro-4-(trifluoromethyl)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-cyanoquinoxalin-6-yl)oxy)-4-fluorophenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-((3-cyanoquinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-((2-methoxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chlorophenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(4-fluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   3-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide-   3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)-4-(trifluoromethyl)benzamide-   4-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(3-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-cyanoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)benzamide-   N-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-fluorobenzamide-   4-chloro-3-fluoro-N-(3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-fluorobenzamide,-   3-fluoro-N-(3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   3-fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-4-(trifluoromethyl)benzamide-   4-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(4-fluoro-3-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(4-fluoro-3-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-cyanoquinoxalin-6-yl)oxy)-4-fluorophenyl)-3-fluorobenzamide-   3-chloro-N-(4-fluoro-3-((3-methoxyquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-4-chloro-3-fluorobenzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-4-chloro-3-fluorobenzamide-   3-fluoro-N-(4-fluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-fluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-fluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(4-fluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-fluoro-5-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-cyanoquinoxalin-6-yl)oxy)-5-fluorophenyl)-3-fluorobenzamide-   3-chloro-N-(3-fluoro-5-((3-methoxyquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-5-fluorophenyl)-4-chloro-3-fluorobenzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-5-fluorophenyl)-4-chloro-3-fluorobenzamide-   3-fluoro-N-(3-fluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-fluorobenzamide-   N-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3,4-difluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(2-chloro-4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2-chloro-4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2-chloro-4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-fluorobenzamide-   3-fluoro-N-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2,4,5-trifluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(3,4-difluoro-5-((3-methylquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2-chloro-4-fluoro-3-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(3-((3-cyanoquinoxalin-6-yl)oxy)-4,5-difluorophenyl)-3-fluorobenzamide-   N-(2-chloro-3-((3-cyanoquinoxalin-6-yl)oxy)-4-fluorophenyl)-3-fluorobenzamide-   N-(3-((3-cyanoquinoxalin-6-yl)oxy)-2,4,5-trifluorophenyl)-3-fluorobenzamide-   3-chloro-N-(3,4-difluoro-5-((3-methoxyquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2-chloro-4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2-chloro-4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2-chloro-4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2,4,5-trifluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2-chloro-4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2-chloro-4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2-chloro-4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2-chloro-4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2,4,5-trifluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3,4-difluoro-5-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2-chloro-4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2-chloro-4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(2-chloro-4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2-chloro-4-fluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2,4,5-trifluoro-3-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-4,5-difluorophenyl)-4-chloro-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-4,5-difluorophenyl)-4-chloro-3-fluorobenzamide-   N-(3,4-difluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(3,4-difluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3,4-difluoro-5-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3,4-difluoro-5-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(3-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-2,4,5-trifluorophenyl)-4-chloro-3-fluorobenzamide-   4-chloro-3-fluoro-N-(2,4,5-trifluoro-3-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2,4,5-trifluorophenyl)-4-chloro-3-fluorobenzamide-   3-fluoro-N-(2,4,5-trifluoro-3-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2,4,5-trifluoro-3-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-((4-methylpiperazin-1-yl)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(3-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3,4-difluorophenyl)urea-   1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-((3-(aminomethyl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-((4-methylpiperazin-1-yl)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-fluoro-3-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(3-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-4-fluorophenyl)-3-(3,4-difluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   N-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide-   N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide-   N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide-   N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide-   N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide-   1-(3,4-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-propyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-cyclopropyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-cyanoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(6-(piperazin-1-yl)pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-(4-(piperazin-1-yl)phenyl)quinoxalin-6-yl)oxy)phenyl)urea-   N-(4-(7-(4-(3-(3-fluorophenyl)ureido)phenoxy)quinoxalin-2-yl)phenyl)methanesulfonamide,-   1-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-cyanoquinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-chlorophenyl)-3-(2-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(2-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(2-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,5-difluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,5-difluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluorophenyl)-3-(2,3,5-trifluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-4-(trifluoromethyl)benzamide-   N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-cyanoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-4-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-(3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-(3-(6-(piperazin-1-yl)pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-(3-(4-(piperazin-1-yl)phenyl)quinoxaline-6-carbonyl)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(4-((3-(4    (methylsulfonamido)phenyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)benzamide-   3-chloro-N-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)benzamide-   N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3,5-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(2,3-difluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)benzamide-   4-chloro-N-(2,3,5-trifluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-(2-hydroxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(2-aminoethoxy)quinoxalin-6-yl)oxy)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-(2-methoxyethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-cyanoquinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3,5-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-3-fluoro-N-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2,3,5-trifluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,3-difluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-3-fluoro-N-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2-fluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3,5-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-fluoro-N-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(2,3,5-trifluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-chloro-N-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(2,3-difluoro-4-((3-(pyrrolidin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(3,5-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-chloro-N-(2,3,5-trifluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   N-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-chloro-N-(2,3-difluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(2-fluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3,5-difluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   3-fluoro-N-(2,3,5-trifluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(2,3-difluoro-4-((3-(6-methylpyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-fluorobenzamide-   4-chloro-N-(3-fluoro-4-((3-(pyridin-3-yl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-4-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-(1H-imidazol-1-yl)quinoxalin-6-yl)oxy)-2-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(2-fluoro-4-((3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2-fluorophenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2-fluorophenyl)-3-fluorobenzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2,3-difluorophenyl)-3-fluorobenzamide-   N-(4-((3-(1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)-2,3-difluorophenyl)-3-(trifluoromethyl)benzamide-   3-fluoro-N-(3-fluoro-4-((3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl)oxy)phenyl)benzamide-   1-(4-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3,4-difluorophenyl)urea-   1-(4-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-cyanophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-chlorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3,4-difluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-fluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3,4-difluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-chloro-4-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-chloro-3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluorophenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluorophenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-methoxyphenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-((4-methylpiperazin-1-yl)methyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(3-morpholinopropoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(2-morpholinoethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chlorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3,4-difluorophenyl)urea-   1-(4-chlorophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-fluorophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chloro-4-cyanophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-dichlorophenyl)-3-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3-methoxyquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-cyanophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-chlorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-methoxyphenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3,4-difluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-fluorophenyl)urea-   1-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-methylquinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3,4-difluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-chloro-4-fluorophenyl)urea-   1-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-chloro-3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea-   1-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-chloro-4-fluorophenyl)-3-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(3-chlorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(3-fluorophenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-methoxyphenyl)urea-   1-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-((dimethylamino)methyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-cyanophenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-chlorophenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea-   1-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-methoxyphenyl)urea-   1-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(3,4-difluorophenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-fluorophenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((3-(4-methylpiperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea-   1-(3-fluoro-4-((3-(3-morpholinopropoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   1-(3-fluoro-4-((3-(2-morpholinoethoxy)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea-   N-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-(trifluoromethyl)benzamide-   3,4-difluoro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-fluoro-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-cyano-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-methoxy-N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)phenyl)-3,4-difluorobenzamide-   3,4-difluoro-N-(4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)phenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-N-(4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3,4-difluoro-N-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-fluoro-N-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(4-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-((3-(1H-pyrazol-1-yl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide-   3,4-difluoro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   4-fluoro-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-cyano-N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide-   N-(3-fluoro-4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-4-methoxybenzamide-   N-(4-((3-(aminomethyl)quinoxalin-6-yl)oxy)-3-fluorophenyl)-3,4-difluorobenzamide-   3,4-difluoro-N-(3-fluoro-4-((3-(piperazin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   N-(4-((3-((2-aminoethyl)amino)quinoxalin-6-yl)oxy)-3-fluorophenyl)-4-chloro-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-((2-hydroxyethyl)amino)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   3,4-difluoro-N-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-fluoro-N-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-N-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   4-chloro-3-fluoro-N-(3-fluoro-4-((3    (morpholinomethyl)quinoxalin-6-yl)oxy)phenyl)benzamide-   4-chloro-N-(3-fluoro-4-((3-(pyrrolidin-1-ylmethyl)quinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide-   N-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea-   1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-fluorophenyl)urea-   1-(4-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea-   1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea-   N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-5-(trifluoromethyl)nicotinamide-   N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-2-(trifluoromethyl)isonicotinamide-   1-(4-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea and-   1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea    and pharmaceutically acceptable salts thereof.

In yet another aspect, the present disclosure provides a compound chosenfrom the compounds set forth in Table 1 below and pharmaceuticallyacceptable salts thereof.

TABLE 1 Illustrative Compounds of the Present Invention Compound No.Chemical Name C0011-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0021-(3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0031-(3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluorometh- yl)phenyl)ureaC004 3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide C005N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluorometh- yl)benzamide C0064-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoro- methyl)benzamideC007 N-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide C0084-chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide C0091-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0104-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phe-nyl)-3-(trifluoromethyl)benzamide C0111-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea C012N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)propane-1-sulfonamide C013N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)propane- 1-sulfonamide C0143-fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phe- nyl)benzamide C015N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(tri- fluoromethyl)benzamideC016 4-chloro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phe-nyl)-3-(trifluoromethyl)benzamide C0173-fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phe- nyl)benzamide C018N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3- (trifluoromethyl)benzamideC019 N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)propane- 1-sulfonamideC020 1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3- fluorophenyl)ureaC021 1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C0221-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea C0231-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3- fluorophenyl)urea C0241-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C0253-fluoro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide C026N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(trifluoromethyl)benzamide C027 3-fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin- 6-yl)oxy)phenyl)benzamide C028N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(trifluoromethyl)benzamide C0294-chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide C030N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)propane-1-sulfonamide C0311-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(3-fluorophenyl)urea C0321-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(3-(trifluoromethyl)phenyl)urea C0331-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0341-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(3-fluorophenyl)urea C0351-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(3-(trifluoromethyl)phenyl)urea C0361-(3,4-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0371-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0381-(4-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C039 1-(3,5-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0401-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C0411-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0421-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin- 6-yl)oxy)phenyl)ureaC043 1-(4-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0441-(3,4-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0451-(3,5-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0461-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C0471-(3-chlorophenyl)-3-(3-((3-morpholinoquinoxalin- 6-yl)oxy)phenyl)ureaC048 1-(4-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C049 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0501-(3-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0511-(4-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C052 1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0531-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phe-nyl)-3-(4-fluorophenyl)urea C0541-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0551-(3-chlorophenyl)-3-(4-fluoro-3-((3-morpholino-quinoxalin-6-yl)oxy)phenyl)urea C0561-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-morpholino-quinoxalin-6-yl)oxy)phenyl)urea C0571-(4-chlorophenyl)-3-(4-fluoro-3-((3-morpholino-quinoxalin-6-yl)oxy)phenyl)urea C0581-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0591-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phe-nyl)-3-(3-fluorophenyl)urea C0601-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phe-nyl)-3-(4-fluorophenyl)urea C0611-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin- 1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0621-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0631-(3-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0641-(4-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0651-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea C0661-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0671-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0681-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0691-(4-methoxyphenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0701-(4-cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0711-propyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0721-cyclopropyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0731-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea C0741-(3-fluorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea C0751-(4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoro- methyl)phenyl)ureaC076 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea C0773-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide C078N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoro- methyl)benzamide C0794-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoro- methyl)benzamideC080 N-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide C0811-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6- yl)oxy)phenyl)ureaC082 1-(4-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0831-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea C0841-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0851-(4-chlorophenyl)-3-(4-((3-morpholinoquinoxalin- 6-yl)oxy)phenyl)ureaC086 1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea C0871-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0881-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea C0891-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0901-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0911-(3-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0921-(4-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea C0931-(3-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6- yloxy)phenyl)urea C0941-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-fluoro- phenyl)urea C0951-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea C0961-(4-chlorophenyl)-3-(2-fluoro-4-(quinoxalin- 6-yloxy)phenyl)urea C0971-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea C0981-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea C099N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-5-(trifluoro-methyl)nicotinamide C100N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-2-trifluoro-methyl)isonicotinamide C1011-(3-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6- yloxy)phenyl)urea C1021-(4-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6- yloxy)phenyl)urea C1031-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea

In some embodiments, a compound of Formula I or II binds to a kinaseincluding, but not limited to, Ab1, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof. Forexample, the compound of Formula I or II binds to a kinase selected fromthe group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-RafV600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1,Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src and Ret, andany mutated versions thereof. In some embodiments, the compound ofFormula I or II binds to a kinase selected from the group consisting ofA-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, orKDR. For example, the compound of Formula I or II binds to a kinasewhich is B-Raf or B-Raf V600E mutant. In some embodiments, a compound ofFormula I or II binds to a kinase including, but not limited to, Ab1,Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5,CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak,FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha,Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk,Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2,MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1,Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2,Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, includingany mutated versions thereof, with a Kd which is lower than 500 μM, 250μM, 50 μM, 25 μM, 10 μM, 5 μM, or 1 μM as measured in an in vitro assay.For example, the compound of Formula I or II binds to a kinase selectedfrom the group consisting of A-Raf, B-Raf, c-Raf-1, Fak, FGFR1, FGFR2,FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2,KDR, Src and Ret, and any mutated versions thereof with a Kd which islower than 500 μM, 250 μM, 50 μM, 25 μM, 10 μM, 5 μM, or 1 μM asmeasured in an in vitro assay. In some embodiments, the compound ofFormula I or II binds to a kinase selected from the group consisting ofA-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, orKDR with a Kd which is lower than 500 μM, 250 μM, 50 μM, 25 μM, 10 μM, 5μM, or 1 μM as measured in an in vitro assay. For example, the compoundof Formula I or II binds to a kinase which is B-Raf or B-Raf V600Emutant with a Kd which is lower than 50 μM, 25 μM, 10 μM, 5 μM, or 1 μMas measured in an in vitro assay.

In some embodiments, a compound of Formula I or II inhibits a kinaseincluding, but not limited to, Ab1, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf,B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR,EphA1, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1,Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2,Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2,Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1,MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta,PKC theta, Plk1, Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2,TrkA, TrkB, Yes, and Zap70, including any mutated versions thereof. Forexample, the compound of Formula I or II inhibits a kinase selected fromthe group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-RafV600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1,Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Src and Ret, andany mutated versions thereof. In some embodiments, the compound ofFormula I or II inhibits a kinase selected from the group consisting ofA-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, orKDR. For example, the compound of Formula I or II inhibits a kinasewhich is B-Raf or B-Raf V600E mutant. In some embodiments, a compound ofFormula I or II inhibits a kinase including, but not limited to, Ab1,Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5,CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2, EphB4, Erk2, Fak,FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms, Frk, Fyn, Gsk3alpha,Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKK beta, Irak4, Itk,Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck, Lyn, MAP2K1, MAP2K2,MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Pim1,Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, ROCK1, ROCK2,Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and Zap70, includingany mutated versions thereof with an IC₅₀ in an in vitro assay of 1000μM, 100 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25nM or less as ascertained in an in vitro kinase assay. For example, thecompound of Formula I or II inhibits a kinase selected from the groupconsisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Jnk1, Jnk2, Jnk3, Lck,Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, PDGFRB, Src and Ret, and anymutated versions thereof with an IC₅₀ in an in vitro assay of 1000 μM,100 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM orless as ascertained in an in vitro kinase assay. In some embodiments,the compound of Formula I or II inhibits a kinase selected from thegroup consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291mutant, c-Raf-1, and KDR with an IC₅₀ in an in vitro assay of 1000 μM,100 μM, 10 μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM orless as ascertained in an in vitro kinase assay. For example, thecompound of Formula I or II inhibits a kinase which is B-Raf or B-RafV600E mutant with an IC₅₀ in an in vitro assay of 1000 μM, 100 μM, 10μM, 5 μM, 2 μM, 1 μM, 500 nM, 200 nM, 100 nM, 50 nM, 25 nM or less asascertained in an in vitro kinase assay.

In some embodiments, the compound of Formula I or II inhibits theactivity of one or more kinases selected from the group consisting ofA-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, andKDR with an IC₅₀ in an in vitro assay of 10 μM, 1 μM, 500 nM, 200 nM,100 nM, 50 nM, 25 nM or less as ascertained in an in vitro kinase assay.

In some embodiments, the compound of Formula I or II selectivelyinhibits the activity of one or more kinases selected from the groupconsisting of Ab1, Akt1, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk,Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-1, Csk, EGFR, EphA1, EphA2, EphB2,EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Flt1, Flt3, Flt4, Fms,Frk, Fyn, Gsk3alpha, Gsk3beta, HCK, Her2/Erbb2, Her4/Erbb4, IGF1R, IKKbeta, Irak4, Itk, Jak1, Jak2, Jak3, Jnk1, Jnk2, Jnk3, KDR, Kit, Lck,Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnk1, MLK1, p38, PDGFRA,PDGFRB, PDPK1, Pim1, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1,Pyk2, ROCK1, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, andZap70, including any mutated versions thereof. For example, the compoundof Formula I or II selectively inhibits the activity of one or morekinases selected from the group consisting of A-Raf, B-Raf, B-Raf V600Emutant, B-Raf V600E/T5291 mutant, c-Raf-1, Fak, FGFR1, FGFR2, FGFR3,FGFR4, Jnk1, Jnk2, Jnk3, Lck, Lyn, Met, Pim1, Pim2, Pim3, Pyk2, KDR, Srcand Ret. In some embodiments, the compound of Formula I or IIselectively inhibits the activity of one or more kinases selected fromthe group consisting of A-Raf, B-Raf, B-Raf V600E mutant, B-RafV600E/T5291 mutant, c-Raf-1, and KDR.

In some embodiments, the compound of Formula I or II selectivelyinhibits the activity of B-Raf, B-Raf V600E mutant or KDR relative toone or more kinases selected from the group consisting of ABL1, AKT1(PKB alpha), AURKB (Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1),CSF1R (FMS), CSNK1G2 (CK1 gamma 2), EGFR (ErbB1), FGFR1, FGR, FLT3,FRAP1 (mTOR), FYN, IGF1R, IKBKB (IKK beta), INSR, KIT, LCK, LYN A,MAP2K1 (MEK1), MAP4K5 (KHS1), MAPK1 (ERK2), MAPK14 (p38 alpha),MAPKAPK2, MET (cMet), PDGFRB (PDGFR beta), PIK3CA/PIK3R1 (p110 alpha/p85alpha)PRKCB2 (PKC beta II), PTK2B (FAK2), PTK6 (Brk), RAFT (cRAF) Y340DY341D, RET, RPS6KB1 (p70S6K), SRC, SRMS (Srm), and YES1. In someembodiments, the compound of Formula I or II selectively inhibits theactivity of one or more kinases selected from the group consisting ofA-Raf, B-Raf, B-Raf V600E mutant, B-Raf V600E/T5291 mutant, c-Raf-1, andKDR with an IC₅₀ which is ½, ⅓^(rd), ¼^(th), ⅕^(th), 1/7^(th),1/10^(th), 1/15^(th), 1/20^(th), 1/25^(th), 1/30^(th), 1/40^(th),1/50^(th), 1/100^(th), 1/150^(th), 1/200^(th), 1/300, 1/400^(th),1/500^(th), 1/1000^(th), 1/2000^(th) or less than the IC₅₀ for a kinaseselected from the group consisting of ABL1, AKT1 (PKB alpha), AURKB(Aurora B), BLK, BTK, CDK1/cyclin B, CHEK1 (CHK1), CSF1R (FMS), CSNK1G2(CK1 gamma 2), EGFR (ErbB1), FGFR1, FGR, FLT3, FRAP1 (mTOR), FYN, IGF1R,IKBKB (IKK beta), INSR, KIT, LCK, LYN A, MAP2K1 (MEK1), MAP4K5-(KHS1),MAPK1 (ERK2), MAPK14 (p38 alpha), MAPKAPK2, MET (cMet), PDGFRB (PDGFRbeta), PIK3CA/PIK3R1 (p110 alpha/p85 alpha)PRKCB2 (PKC beta II), PTK2B(FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET, RPS6KB1 (p70S6K), SRC,SRMS (Srm), and YES1.

In some embodiments, one or more compounds of Formula I or II arecapable of inhibiting cellular proliferation. For example, in somecases, one or more compounds of Formula I or II inhibit proliferation oftumor cells or tumor cell lines. For example, such cell lines express akinase which is B-raf or B-raf V600E mutant. In some cases, thecompounds of Formula I or II inhibit A375, Colo205 or A549 cellproliferation in vitro or in an in vivo model such as a xenograft mousemodel. In some cases, in vitro cultured A375 or A549 cell proliferationmay be inhibited with an IC₅₀ of less than 1000 μM, 100 μM, 75 μM, 50μM, 25 μM, 15 μM, 10 μM, 5 μM, 3 μM, 2 μM, 1 μM, 0.5 μM, 0.1 μM or lessby one or more compounds of Formula I or II, such as the compoundslisted in Table 1.

B. Methods of Making

Compounds disclosed herein may be prepared by the routes describedbelow. Materials used herein are either commercially available orprepared by synthetic methods generally known in the art. These schemesare not limited to the compounds listed or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps of are described and depicted in Schemes A and B, thesteps in some cases may be performed in a different order than the ordershown in Schemes A and B. Various modifications to these syntheticreaction schemes may be made and will be suggested to one skilled in theart having referred to the disclosure contained in this Application.Numbering does not necessarily correspond to that of claims or othertables.

As shown in Schemes A and B, bromo compound A-1 is reacted with phenolA-2 or A-5 in the presence of base to afford A-3 or A-6. Suitable basesfor carrying out the reaction include, but are not limited to, K₂CO₃, orCs₂CO₃, and the like. Suitable solvents include, but are not limited to,DMF, DMSO, tetrahydrofuran, and a mixture thereof. After removing theprotecting group in A-3 or A-6, the anilino nitrogen is derivatized togive target compound of Formula I or II. Examples of protecting groupinclude, but are not limited to —C(═O)Ot-Bu and —C(═O)t-Bu. Thedeprotection can be carried out with strong acids, such as HCl, HBr,trifluoroaceti acid, and H₂SO₄, or strong bases, such as NaOH, KOH, orCsOH.

C. Pharmaceutical Compositions and Formulations

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofFormula I or II, and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In certain embodiments, the compoundsdescribed are administered as pharmaceutical compositions in whichcompounds of Formula I or II, are mixed with other active ingredients,as in combination therapy. Encompassed herein are all combinations ofactives set forth in the combination therapies section below andthroughout this disclosure. In specific embodiments, the pharmaceuticalcompositions include one or more compounds of Formula I or II.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula I or II, with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In certain embodiments, thepharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compounds ofFormula I or II, provided herein are administered in a pharmaceuticalcomposition to a mammal having a disease or condition to be treated. Inspecific embodiments, the mammal is a human. In certain embodiments,therapeutically effective amounts vary depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds described herein are usedsingly or in combination with one or more therapeutic agents ascomponents of mixtures.

In one embodiment, one or more compounds of Formula I or II, isformulated in an aqueous solution. In specific embodiments, the aqueoussolution is selected from, by way of example only, a physiologicallycompatible buffer, such as Hank's solution, Ringer's solution, orphysiological saline buffer. In other embodiments, one or more compoundof Formula I or II, is formulated for transmucosal administration. Inspecific embodiments, transmucosal formulations include penetrants thatare appropriate to the barrier to be permeated. In still otherembodiments wherein the compounds described herein are formulated forother parenteral injections, appropriate formulations include aqueous ornonaqueous solutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein, including compounds ofFormula I or II, are formulated by combining the active compounds with,e.g., pharmaceutically acceptable carriers or excipients. In variousembodiments, the compounds described herein are formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical composition of a compound of Formula Ior II is formulated in a form suitable for parenteral injection assterile suspension, solution or emulsion in oily or aqueous vehicles.Parenteral injection formulations optionally contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. In specificembodiments, pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.In additional embodiments, suspensions of the active compounds areprepared as appropriate oily injection suspensions. Suitable lipophilicsolvents or vehicles for use in the pharmaceutical compositionsdescribed herein include, by way of example only, fatty oils such assesame oil, or synthetic fatty acid esters, such as ethyl oleate ortriglycerides, or liposomes. In certain specific embodiments, aqueousinjection suspensions contain substances which increase the viscosity ofthe suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. Alternatively, in otherembodiments, the active ingredient is in powder form for constitutionwith a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In still other embodiments, the compounds of Formula I or II areadministered topically. The compounds described herein are formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams or ointments. Such pharmaceutical compositions optionally containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

In yet other embodiments, the compounds of Formula I or II areformulated for transdermal administration. In specific embodiments,transdermal formulations employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In various embodiments, such patches are constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.In additional embodiments, the transdermal delivery of the compounds ofFormula I or II, is accomplished by means of iontophoretic patches andthe like. In certain embodiments, transdermal patches provide controlleddelivery of the compounds of Formula I or II. In specific embodiments,the rate of absorption is slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. In alternativeembodiments, absorption enhancers are used to increase absorption.Absorption enhancers or carriers include absorbable pharmaceuticallyacceptable solvents that assist passage through the skin. For example,in one embodiment, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In other embodiments, the compounds of Formula I or II, are formulatedfor administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of Formula I or II, areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant(e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In still other embodiments, the compounds of Formula I or II, areformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are optionally used as suitable. Pharmaceuticalcompositions comprising a compound of Formula I or II, are manufacturedin a conventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofFormula I or II, described herein as an active ingredient. The activeingredient is in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of N-oxides, crystallineforms (also known as polymorphs), as well as active metabolites of thesecompounds having the same type of activity. All tautomers of thecompounds described herein are included within the scope of thecompounds presented herein. Additionally, the compounds described hereinencompass unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In addition, the pharmaceutical compositionsoptionally include other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, a pharmaceutical composition comprising at leastone compound of Formula I or II, illustratively takes the form of aliquid where the agents are present in solution, in suspension or both.Typically when the composition is administered as a solution orsuspension a first portion of the agent is present in solution and asecond portion of the agent is present in particulate form, insuspension in a liquid matrix. In some embodiments, a liquid compositionincludes a gel formulation. In other embodiments, the liquid compositionis aqueous.

In certain embodiments, useful aqueous suspension contain one or morepolymers as suspending agents. Useful polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein comprise a mucoadhesive polymer, selected for examplefrom carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of Formula Ior II. The term “solubilizing agent” generally includes agents thatresult in formation of a micellar solution or a true solution of theagent. Certain acceptable nonionic surfactants, for example polysorbate80, are useful as solubilizing agents, as can ophthalmically acceptableglycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

D. Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

E. Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products Includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. The container(s) optionally have a sterile accessport (for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical compositions is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack for example contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

F. Methods of Use

The chemical entities described herein are useful in the treatment, orin the preparation of a medicament for the treatment of variousdisorders. For example, compounds of Formula I or II are useful asinhibitors of protein kinases. In some embodiments, the chemicalentities described herein are inhibitors of one or more kinases. Forexample, compounds of Formula I or II are inhibitors of A-Raf, B-Raf,C-Raf, KDR and of mutants of such kinases, including the B-Raf V600Emutant. Thus, without wishing to be bound by any particular theory, thecompounds of Formula I or II are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation of one or more kinases, such as Raf kinases, which isimplicated in the disease, condition, or disorder. When activation ofRaf kinases is implicated in a particular disease, condition, ordisorder, the disease, condition, or disorder may also be referred to as“Raf-mediated disease” or disease symptom. Accordingly, in anotheraspect, the present invention provides a method for treating orlessening the severity of a disease, condition, or disorder whereactivation or one or more of Raf kinases is implicated in the diseasestate.

In some embodiments, the chemical entities described herein areinhibitors of KDR. Inhibition of KDR leads to inhibition ofVEGF-mediated angiogenesis. Accordingly, in another aspect, the presentinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where diseases are characterized byabnormal angiogenesis.

The inhibition of kinases may be assayed in vitro, in vivo or in a cellline. In vitro assays include assays that determine inhibition of eitherthe phosphorylation activity or ATPase activity of activated kinase.Alternate in vitro assays quantitate the ability of the inhibitor tobind to kinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor, complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with kinase bound to known radioligands. At 1micro-molar concentration, one or more compounds of the presentinvention exhibits at least about 50%, 60%, 70, 80%, 90% or even higherinhibition of kinases including B-Raf, B-Raf V600E mutant and KDR.

The chemical entities described herein may be prepared in substantiallypure form, typically by standard chromatographic methods, prior toformulation in a pharmaceutically acceptable form.

The chemical entities described herein may be used in treating a varietyof cancers. Cancers that can be prevented and/or treated by the chemicalentities, compositions, and methods described herein include, but arenot limited to, human sarcomas and carcinomas, e.g. carcinomas, e.g.,colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonalcarcinoma, Wilms' tumor, cervical cancer, testicular tumor, lungcarcinoma, small cell lung carcinoma, bladder carcinoma, epithelialcarcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma,ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma,leukemias, e.g., acute lymphocytic leukemia and acute myelocyticleukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic anderythroleukemia); chronic leukemia (chronic myelocytic (granulocytic)leukemia and chronic lymphocytic leukemia); and polycythemia vera,lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiplemyeloma, Waldenstrom's macroglobulinemia, and heavy chain disease.

In some embodiments, the chemical entities described herein are used forthe treatment of cancers of the

-   -   i. digestive system including, without limitation, the        esophagus, stomach, small intestine, colon (including        colorectal), liver & intrahepatic bile duct, gallbladder & other        biliary, pancreas, and other digestive organs;    -   ii. respiratory system, including without limitation, larynx,        lung & bronchus, and other respiratory organs;    -   iii. skin;    -   iv. thyroid;    -   v. breast;    -   vi. genital system, including without limitation, uterine        cervix, ovary, and prostate;    -   vii. urinary system, including without limitation, urinary        bladder and kidney and renal pelvis; and    -   viii. oral cavity & pharynx, including without limitation,        tongue, mouth, pharynx, and other oral cavity.

In some embodiments, the chemical entities described herein are used forthe treatment of colon cancer, liver cancer, lung cancer, melanoma,thyroid cancer, breast cancer, ovarian cancer, and oral cancer.

The chemical entities described herein may also be used in conjunctionwith other well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the chemical entities described herein may be useful incombination with at least one additional anti-cancer and/or cytotoxicagents. Further, the chemical entities described herein may also beuseful in combination with other inhibitors of parts of the signalingpathway that links cell surface growth factor receptors to nuclearsignals initiating cellular proliferation.

Such known anti-cancer and/or cytotoxic agents that may be used incombination with the chemical entities described herein include:

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumorantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5a-reductase suchas finasteride;

(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy)-5-tetrahydropyran-4yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chern., 2004, 47, 66586661) andbosutinib (SK1-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];

(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB 1 antibody cetuximab[Erbitux, C225] and any growth factor or growth factor receptorantibodies disclosed by Stem et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (RI15777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-IR kinaseinhibitors, IGF receptor (insulin like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-{4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO 97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin av˜3 function andangiostatin));

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;

(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase subject tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of subject's tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell energy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

In certain embodiments, the at least one chemical entity is administeredin combination with one or more agents chosen from pacliataxel,bortezomib, dacarbazine, gemcitabine, trastuzumab, bevacizumab,capecitabine, docetaxel, erlotinib, aromatase inhibitors, such asAROMASIN™ (exemestane), and estrogen receptor inhibitors, such asFASLODEX™ (fulvestrant).

When a chemical entity described herein is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual subject, as well as the severityof the subject's symptoms.

In one exemplary application, a suitable amount of at least one chemicalentity is administered to a mammal undergoing treatment for cancer, forexample, breast cancer. Administration typically occurs in an amount ofbetween about 0.01 mg/kg of body weight to about 100 mg/kg of bodyweight per day (administered in single or divided doses), such as atleast about 0.1 mg/kg of body weight per day. A particular therapeuticdosage can include, e.g., from about 0.01 mg to about 1000 mg of thechemical entity, such as including, e.g., from about 1 mg to about 1000mg. The quantity of the at least one chemical entity in a unit dose ofpreparation may be varied or adjusted from about 0.1 mg to 1000 mg, suchas from about 1 mg to 300 mg, for example 10 mg to 200 mg, according tothe particular application. The amount administered will vary dependingon the particular IC₅₀ value of the at least one chemical entity usedand the judgment of the attending clinician taking into considerationfactors such as health, weight, and age. In combinational applicationsin which the at least one chemical entity described herein is not thesole active ingredient, it may be possible to administer lesser amountsof the at least one chemical entity and still have therapeutic orprophylactic effect.

In some embodiments, the pharmaceutical preparation is in unit dosageform. In such form, the preparation is subdivided into unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The actual dosage employed may be varied depending upon the requirementsof the subject and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the at least onechemical entity. Thereafter, the dosage is increased by small amountsuntil the optimum effect under the circumstances is reached. Forconvenience, the total daily dosage may be divided and administered inportions during the day if desired.

The amount and frequency of administration of the at least one chemicalentities described herein, and if applicable other chemotherapeuticagents and/or radiation therapy, will be regulated according to thejudgment of the attending clinician (physician) considering such factorsas age, condition and size of the subject as well as severity of thedisease being treated.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thesubject, and in view of the observed responses of the disease to theadministered therapeutic agents.

Also, in general, the at least one chemical entities described hereinneed not be administered in the same pharmaceutical composition as achemotherapeutic agent, and may, because of different physical andchemical characteristics, be administered by a different route. Forexample, the chemical entities/compositions may be administered orallyto generate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of chemical entity (and where appropriate,chemotherapeutic agent and/or radiation) will depend upon the diagnosisof the attending physicians and their judgment of the condition of thesubject and the appropriate treatment protocol.

The chemical entities described herein (and where appropriatechemotherapeutic agent and/or radiation) may be administeredconcurrently (e.g., simultaneously, essentially simultaneously or withinthe same treatment protocol) or sequentially, depending upon the natureof the proliferative disease, the condition of the subject, and theactual choice of chemotherapeutic agent and/or radiation to beadministered in conjunction (i.e., within a single treatment protocol)with the chemical entity/composition.

In combinational applications and uses, the chemical entity/compositionand the chemotherapeutic agent and/or radiation need not be administeredsimultaneously or essentially simultaneously, and the initial order ofadministration of the chemical entity/composition, and thechemotherapeutic agent and/or radiation, may not be important. Thus, theat least one chemical entity described herein may be administered firstfollowed by the administration of the chemotherapeutic agent and/orradiation; or the chemotherapeutic agent and/or radiation may beadministered first followed by the administration of the at least onechemical entity described herein. This alternate administration may berepeated during a single treatment protocol. The determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is well withinthe knowledge of the skilled physician after evaluation of the diseasebeing treated and the condition of the subject. For example, thechemotherapeutic agent and/or radiation may be administered first, andthen the treatment continued with the administration of the at least onechemical entity described herein followed, where determinedadvantageous, by the administration of the chemotherapeutic agent and/orradiation, and so on until the treatment protocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a chemicalentity/composition for treatment according to the individual subject'sneeds, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thesubject as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radiological studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe invention. These examples are presented for illustrative purposesand should not serve to limit the true scope of the invention.

In carrying out the procedures of the methods described herein, it is ofcourse to be understood that reference to particular buffers, media,reagents, cells, culture conditions and the like are not intended to belimiting, but are to be read so as to include all related materials thatone of ordinary skill in the art would recognize as being of interest orvalue in the particular context in which that discussion is presented.For example, it is often possible to substitute one buffer system orculture medium for another and still achieve similar, if not identical,results. Those of skill in the art will have sufficient knowledge ofsuch systems and methodologies so as to be able, without undueexperimentation, to make such substitutions as will optimally servetheir purposes in using the methods and procedures disclosed herein.

Example 1: Preparation of1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

To a solution of quinoxalin-2(1H)-one (54.64 g, 374 mmol, 1.0 eq.) inHOAc (1000 mL) was added a solution of Br₂ (19.18 mL, 374 mmol, 1.0 eq.)in HOAc (200 mL) dropwise. The resulting mixture was stirred at roomtemperature for 12 h, then poured into ice-water. The precipitate wascollected by filtration and dried to afford 7-bromoquinoxalin-2(1H)-one(74 g, 88%).

To a suspension of 7-bromoquinoxalin-2(1H)-one (224 g, 1 mol, 1.0 eq.)in POCl₃-(1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). Theresulting mixture was stirred at 120° C. for 2 h, then cooled to roomtemperature and slowly poured into ice-water with vigorous stirring. Theprecipitate was collected by filtration and dried to afford7-bromo-2-chloroquinoxaline (180 g, 75%).

To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2 mol, 1.0 eq.) inCH₃CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K₂CO₃(85 g, 0.61 mol, 3.0 eq). The resulting mixture was stirred at 90° C.for 2 h, then cooled and filtered. The filtrate was concentrated and theresulting residue was re-crystallized in ethyl acetate to afford4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3%).

To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (2.95 g, 0.01 mol,1.0 eq.) and N-(3-hydroxyphenyl)pivalamide (2.3 g, 0.012 mol, 1.2 eq.)in DMF (100 mL) were added Cs₂CO₃ (9.78 g, 0.03 mol, 3 eq.) and CuI (192mg, 0.001 mol, 0.1 eq.). The resulting mixture was stirred at 120° C.overnight, then cooled and concentrated. The resulting residue wasdissolved in THF (100 mL) and the resulting precipitate was removed byfiltration. The filtrate was concentrated and the resulting residue waspurified by column chromatography (PE/EA=1:1 to EA, v/v) to affordN-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)pivalamide (3.6 g, 88.7%).

To a solution of N-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)pivalamide (3.6 g, 0.89 mol, 1.0 eq.) in HOAc (30 mL) was addedconc. HCl (15 mL). The mixture was stirred at 110° C. for 4 h, thencooled and poured onto ice (100 mL). The mixture was adjusted to pH 10by the addition of NaOH (1 N) solution, then extracted with DCM (100mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated. The resulting residue was purified by columnchromatography (PE/EA=1/2, v/v) to afford3-((3-morpholinoquinoxalin-6-yl)oxy)aniline (1.8 g, 63.2% yield).

To a solution of 3-((3-morpholinoquinoxalin-6-yl)oxy)aniline (100 mg,0.31 mmol, 1.0 eq.) in DCM (5 mL) were added TEA (0.13 mL, 0.93 mmol, 3eq.) and 1-fluoro-3-isocyanatobenzene (63.7 mg, 0.465 mmol, 1.5 eq.).The resulting mixture was stirred at room temperature for 1 h andconcentrated. The resulting residue was purified by flash columnchromatography (PE/EA=1/1, v/v) to afford1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(40.7 mg, 28.7% yield). LRMS (M+H⁺) m/z calculated 460.2, found 460.1.¹H NMR (DMSO-d₆, 300 MHz) δ 8.91 (s, 1H), 8.71 (s, 1H), 7.86 (d, 1H),7.16-7.46 (m, 6H), 7.09 (d, 1H), 6.93 (d, 1H), 6.75-6.80 (m, 2H), 3.71(s, 8H).

Example 2: Preparation of1-(4-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(35.6 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 460.2, found 460.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.84 (s, 1H), 8.70 (d, 2H), 7.85 (d, 1H), 7.32-7.44 (m, 4H), 7.06-7.20(m, 4H), 6.93 (d, 1H), 6.73-6.77 (m, 1H), 3.71 (s, 8H).

Example 3: Preparation of1-(3,4-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-Difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(21.5 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 478.2, found 478.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.91 (d, 2H), 8.71 (s, 1H), 7.86 (d, 1H), 7.60-7.65 (m, 1H), 7.08-7.39(m, 6H), 6.93 (d, 1H), 6.75-6.78 (m, 1H), 3.71 (s, 8H).

Example 4: Preparation of1-(3,5-difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-difluorophenyl)3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-Difluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(32.6 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 478.2, found 478.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.05 (d, 2H), 8.71 (s, 1H), 7.85 (d, 1H), 7.35-7.38 (m, 2H), 7.14-7.23(m, 4H), 6.92 (d, 1H), 6.78-6.80 (m, 2H), 3.71 (s, 8H).

Example 5: Preparation of1-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)3-(3-(trifluoromethyl)phenyl)urea

1-(3-((3-Morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(34.0 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 510.2, found 510.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.91 (d, 2H), 8.71 (s, 1H), 7.96 (s, 1H), 7.85 (d, 1H), 7.16-7.54 (m,7H), 6.92 (d, 1H), 6.76-6.79 (m, 1H), 3.71 (s, 8H).

Example 6: Preparation of1-(3-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(45.6 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 476.1, found 476.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.90 (d, 2H), 8.71 (s, 1H), 7.85 (d, 1H), 7.65-7.66 (m, 1H), 7.34-7.40(m, 2H), 7.17-7.28 (m, 4H), 7.00-7.02 (m, 1H), 6.93 (d, 1H), 6.76-6.79(m, 1H), 3.71 (s, 8H).

Example 7: Preparation of1-(4-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(45.4 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 476.1, found 476.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.85 (d, 2H), 8.71 (s, 1H), 7.85 (d, 1H), 7.28-7.46 (m, 6H), 7.16-7.20(m, 2H), 6.93 (d, 1H), 6.74-6.78 (m, 1H), 3.71 (s, 8H).

Example 8: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(35.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 544.1, found 544.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.18 (s, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.05 (dd, 1H), 7.85 (d, 1H),7.60-7.61 (m, 2H), 7.16-7.40 (m, 4H), 6.92 (d, 1H), 6.77-6.80 (m, 1H),3.71 (s, 8H).

Example 9: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea(37.4 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 459.1, found 459.0. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.20 (s, 1H), 9.06 (s, 1H), 8.89 (d, 2H), 8.49 (s, 1H), 8.16 (d, 1H),8.06 (d, 1H), 7.58-7.70 (m, 3H), 7.40-7.48 (m, 3H), 7.28-7.30 (m, 1H),6.86 (dd, 1H).

Example 10: Preparation of1-(3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(3-fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(3-Fluorophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea (44.4 mg) wasprepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 375.1, found 375.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.87-8.95 (m, 4H), 8.15 (d, 1H), 7.69 (dd, 1H), 7.38-7.47 (m, 4H),7.09-7.11 (m, 1H), 6.75-6.85 (m, 2H).

Example 11: Preparation of1-(3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-(quinoxalin-6-yloxy)phenyl) 3-(3-(trifluoromethyl)phenyl)urea

1-(3-(Quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (32.9mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 425.1, found 425.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.08 (s, 1H), 9.01 (s, 1H), 8.89 (dd, 2H), 8.15 (d, 1H), 7.96 (s, 1H),7.69 (dd, 1H), 7.47-7.57 (m, 3H), 7.31-7.43 (m, 2H), 7.25-7.30 (m, 2H),6.83-6.86 (m, 1H).

Example 12: Preparation of1-(4-methoxyphenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-methoxyphenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Methoxyphenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea (45.7 mg) wasprepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 386.1, found 387.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.80-8.90 (m, 3H), 8.49 (s, 1H), 8.15 (d, 1H), 7.68 (d, 1H), 7.19-7.48(m, 6H), 6.78-6.85 (m, 3H), 3.70 (s, 3H).

Example 13: Preparation of1-(4-cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Cyanophenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea (20.2 mg) wasprepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 382.1, found 382.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.30 (s, 1H), 9.13 (s, 1H), 8.89 (d, 2H), 8.16 (d, 1H), 7.59-7.76 (m,6H), 7.39-7.48 (m, 3H), 7.25-7.28 (m, 1H), 6.85 (d, 1H).

Example 14: Preparation of 1-propyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-propyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-Propyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea (35.5 mg) was prepared asdescribed for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 323.1, found 323.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.88 (dd, 2H), 8.14 (d, 1H), 7.65 (dd, 1H), 7.30-7.44 (m, 3H), 7.12(d, 1H), 6.73 (dd, 1H), 6.17 (t, 1H), 3.00 (q, 2H), 1.36-1.43 (m, 2H),0.84 (t, 3H).

Example 15: Preparation of1-cyclopropyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-cyclopropyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-Cyclopropyl-3-(3-(quinoxalin-6-yloxy)phenyl)urea (27.8 mg) wasprepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 321.1, found 321.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.88 (dd, 2H), 8.50 (s, 1H), 8.14 (d, 1H), 7.65 (dd, 1H), 7.44-7.45(m, 1H), 7.30-7.36 (m, 2H), 7.16 (d, 1H), 6.74 (dd, 1H), 6.42 (s, 1H),0.58-0.61 (m, 2H), 0.37-0.40 (m, 2H).

Example 16: Preparation of1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-(3-(quinoxalin-6-yloxy)phenyl)urea(40.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M−H⁺) m/z calculated 448.1, found 448.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.64 (s, 1H), 9.27 (s, 1H), 8.89 (d, 2H), 8.14-8.17 (m, 2H), 8.02 (d,1H), 7.45-7.77 (m, 1H), 7.67-7.70 (m, 1H), 7.39-7.47 (m, 3H), 7.29-7.31(m, 1H), 6.88 (dd, 1H).

Example 17: Preparation of1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-Fuoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(36.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 443.1, found 443.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.11 (s, 1H), 9.03 (s, 1H), 8.89 (dd, 2H), 8.17 (d, 1H), 7.96 (s, 1H),7.74 (dd, 1H), 7.40-7.63 (m, 4H), 7.29-7.34 (m, 3H).

Example 18: Preparation of1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea

1-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea

1-(4-Fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea (20.8mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 393.1, found 393.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.01 (s, 2H), 8.89 (dd, 2H), 8.17 (d, 1H), 7.74 (dd, 1H), 7.60 (dd,1H), 7.25-7.44 (m, 5H), 7.10 (d, 1H), 6.75-6.80 (m, 1H).

Example 19: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)urea(26.7 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 477.1, found 477.0. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.24 (s, 1H), 9.10 (s, 1H), 8.89 (dd, 2H), 8.17 (d, 1H), 8.06 (d, 1H),7.74 (dd, 1H), 7.59-7.62 (m, 3H), 7.41-7.43 (m, 1H), 7.33-7.34 (m, 2H).

Example 20: Preparation of1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-Fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(18.1 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 528.2, found 528.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.10 (s, 1H), 9.00 (s, 1H), 8.72 (s, 1H), 7.95 (s, 1H), 7.86 (d, 1H),7.49-7.55 (m, 3H), 7.37 (t, 1H), 7.30 (d, 1H), 7.23 (dd, 1H), 6.86 (d,1H).

Example 21: Preparation of1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea

1 (4 fluoro 3-((3-morpholinoquinoxalin 6 yl)oxy)phenyl)3-(3fluorophenyl)urea

1-(4-Fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea(12.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 478.2, found 478.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.99 (t, 2H), 8.72 (s, 1H), 7.87 (d, 1H), 7.53 (dd, 1H), 7.35-7.45 (m,2H), 7.21-7.31 (m, 3H), 7.09 (dd, 1H), 6.86 (d, 1H), 7-6.75-6.79 (m,1H).

Example 22: Preparation of1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-difluorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-Difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(40.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 496.2, found 496.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.94 (d, 2H), 8.72 (s, 1H), 7.88 (d, 1H), 7.57-7.64 (m, 1H), 7.52 (dd,1H), 7.38 (t, 2H), 7.20-7.32 (m, 2H), 7.07-7.13 (m, 1H), 6.85-6.86 (d,1H), 3.67-3.80 (s, 8H).

Example 23: Preparation of1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea

1-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea

1-(4-Fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea(76.8 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 478.2, found 478.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.85 (s, 1H), 8.72 (s, 2H), 7.86 (d, 1H), 7.53 (dd, 1H), 7.39-7.43 (m,3H), 7.20-7.26 (m, 2H), 7.09 (t, 2H), 6.87 (d, 1H), 3.71 (s, 8H).

Example 24: Preparation of1-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-difluorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-Difluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(51.8 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 496.2, found 496.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.06 (d, 2H), 8.72 (s, 1H), 7.87 (d, 1H), 7.52 (dd, 1H), 7.38 (t, 1H),7.12-7.29 (m, 4H), 6.74-6.88 (m, 2H), 3.67-3.82 (s, 8H).

Example 25: Preparation of1-(3-chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(49.9 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 494.1, found 494.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.92 (d, 2H), 8.72 (s, 1H), 7.87 (d, 1H), 7.65 (s, 1H), 7.53 (dd, 1H),7.20-7.41 (m, 5H), 7.02 (d, 1H), 6.86 (d, 1H), 3.72 (s, 8H).

Example 26: Preparation of1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-chloro-4-fluorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(77.0 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 512.1, found 512.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.94 (s, 1H), 8.89 (s, 1H), 7.72 (s, 1H), 7.87 (d, 1H), 7.74 (d, 1H),7.52 (d, 1H), 7.20-7.40 (m, 5H), 6.86 (d, 1H), 3.71 (s, 8H).

Example 27: Preparation of1-(4-chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(56.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 494.1, found 494.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.88 (d, 2H), 8.72 (s, 1H), 7.86 (d, 1H), 7.52 (dd, 1H), 7.44 (d, 2H),7.37 (t, 1H), 7.20-7.32 (m, 4H), 6.87 (d, 1H), 3.69 (s, 8H).

Example 28: Preparation of1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-fluorophenyl) 3-(4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(40.1 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 512.1, found 512.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.06 (s, 1H), 8.99 (s, 1H), 8.72 (s, 1H), 7.87 (d, 1H), 7.61 (d, 1H),7.52 (dd, 1H), 7.36-7.46 (m, 2H), 7.14-7.28 (m, 3H), 6.87 (d, 1H), 3.71(s, 8H).

Example 29: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(37 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 562.1, found 562.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.24 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 8.05 (d, 1H), 7.87 (d, 1H),7.58-7.64 (m, 2H), 7.52 (dd, 1H), 7.37 (t, 1H), 7.27-7.31 (m, 1H),7.21-7.24 (m, 1H), 6.86 (d, 1H), 3.65 (t, 8H).

Example 30: Preparation of1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea

1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl) 3-(3fluorophenyl)urea

1-(3-Fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-fluorophenyl)urea (9.8mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 393.1, found 393.1. ¹H NMR (CD₃OD, 400 MHz) δ8.82-8.85 (m, 2H), 8.16 (d, 2H), 7.69 (d, 1H), 7.51 (d, 1H), 7.37-7.42(m, 1H), 7.22-7.28 (m, 2H), 7.07-7.11 (m, 2H), 6.71-6.78 (m, 1H),6.59-6.63 (m, 1H).

Example 31: Preparation of1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)3-(3-(trifluoromethyl)phenyl)urea

1-(3-Fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(30.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 443.1, found 443.1. ¹H NMR (CDCl₃, 400 MHz) δ8.80 (s, 2H), 8.11 (d, 1H), 7.50-7.59 (m, 4H), 7.31-7.42 (m, 2H), 7.12(d, 1H), 6.98-7.04 (m, 2H), 6.54-6.58 (m, 1H).

Example 32: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl) 3-(3fluoro5-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)urea(35.7 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 477.1, found 477.1. ¹H NMR (CDCl₃, 400 MHz) δ8.80 (s, 2H), 8.12 (d, 1H), 7.51-7.63 (m, 4H), 7.39 (d, 1H), 7.15 (d,2H), 6.98-7.02 (m, 2H), 6.54-6.58 (m, 1H).

Example 33: Preparation of1-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1 (3fluoro5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-Fuoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(58.0 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 528.2, found 528.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.15 (d, 2H), 8.75 (s, 1H), 7.94 (s, 1H), 7.88 (d, 1H), 7.48-7.58 (m,2H), 7.19-7.33 (m, 3H), 7.05 (d, 1H), 7.02 (s, 1H), 6.65-6.68 (m, 1H),3.73 (s, 8H).

Example 34: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl) 3-(3fluoro5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(63.9 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 562.1, found 562.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.25 (d, 2H), 8.75 (s, 1H), 8.04 (d, 1H), 7.88 (d, 1H), 7.59-7.65 (m,2H), 7.19-7.26 (m, 2H), 7.02-7.05 (m, 2H), 6.65-6.69 (m, 1H), 3.73 (s,8H).

Example 35: Preparation of1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-fluorophenyl)3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

To a solution of 7-bromo-2-chloroquinoxaline (7.0 g, 29 mmol, 1.0 eq.)in CH₃CN (150 mL) were added tert-butyl piperazine-1-carboxylate (5.95g, 32 mmol, 1.1 eq.) and K₂CO₃ (12 g, 87 mol, 3.0 eq.). The resultingmixture was stirred at 100° C. for 2 h, then cooled and filtered. Thefiltrate was washed with 10% citric acid (50 mL×3), dried andconcentrated to afford tert-butyl4-(7-bromoquinoxalin-2-yl)piperazine-1-carboxylate (11.3 g, 99%) whichwas used in the next step without further purification.

To a solution of tert-butyl4-(7-bromoquinoxalin-2-yl)piperazine-1-carboxylate (3.63 g, 15 mmol, 1.0eq.) and N-(3-hydroxyphenyl)pivalamide (3.47 g, 18 mmol, 1.2 eq.) in DMF(200 mL) was added CuI (288 mg, 1.5 mmol, 0.1 eq.) and Cs₂CO₃ (14.7 g,45 mmol, 3 eq.). The resulting mixture was stirred at 120° C. overnight,then cooled to room temperature and concentrated. The resulting residuewas dissolved in THF (300 mL) and the resulting solid was removed byfiltration. The filtrate was concentrated and the resulting residue waspurified by column chromatography (PE/EA=1:1 to EA, v/v) to affordtert-butyl tert-butyl4-(7-(3-pivalamidophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (2.8g, 47%).

To a solution of tert-butyl tert-butyl4-(7-(3-pivalamidophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (2.8g, 6.9 mmol, 1.0 eq.) in HOAc (20 mL) was added con. HCl (10 mL). Themixture was stirred at 110° C. for 4 h, then cooled and poured onto ice(100 mL). The resulting mixture was adjusted to pH 10 by the addition ofNaOH (1 N) solution, then extracted with DCM (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated toafford 3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)aniline (2.2 g, ca.100% yield) which was used in the next step without furtherpurification.

To a solution of 3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)aniline (2.2g, 6.9 mmol, 1.0 eq.) in MeOH (30 mL) were added (1.5 g, 6.9 mmol, 1.0eq.) and TEA (6.97 g, 69 mmol, 10 eq.). The resulting mixture wasstirred at room temperature for 0.5 h, then concentrated. The resultingresidue was purified by column chromatography (PE/EA=1/1, v/v) to affordtert-butyl 4-(7-(3-aminophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate(0.6 g, 20%).

To a solution of tert-butyl tert-butyl4-(7-(3-aminophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (110 mg,0.26 mmol, 1.0 eq.) in THF (5 mL) was added DIEA (0.5 mL, 2.5 mmol, 10.0eq.), followed by 1-fluoro-3-isocyanatobenzene (53 mg, 0.39 mmol, 1.5eq.). The resulting mixture was stirred at room temperature for 1.5 hand concentrated. The resulting residue was purified by columnchromatography (PE/EA=1/1, v/v) to afford tert-butyl4-(7-(3-(3-(3-fluorophenyl)ureido)phenoxy)quinoxalin-2-yl)piperazine-1-carboxylate(131 mg, 89.7%)

To a solution of tert-butyl4-(7-(3-(3-(3-fluorophenyl)ureido)phenoxy)quinoxalin-2-yl)piperazine-1-carboxylate(131 mg, 0.22 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL). Theresulting mixture was stirred at room temperature for 1 h, thenconcentrated. The resulting residue was basified to pH 7-8 by theaddition aqueous NaHCO₃ solution and extracted with DCM (20 mL×2). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to afford1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(80.4 mg). LRMS (M+H⁺) m/z calculated 459.2, found 459.2. ¹H NMR(DMSO-d₆, 300 MHz) δ 8.95 (s, 1H), 8.70 (s, 1H), 7.82-7.85 (d, 1H),7.45-7.46 (m, 3H), 7.38-7.42 (m, 1H), 7.08-7.36 (m, 3H), 6.85 (d, 1H),6.74-6.80 (m, 2H), 3.72 (t, 4H), 3.20 (t, 4H).

Example 36: Preparation of1-(3,4-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-Difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(105.9 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H+) m/z calculated 477.2, found 477.1. 1H NMR (DMSO-d₆, 300 MHz)δ 9.05-9.07 (m, 2H), 8.72 (s, 1H), 7.77 (d, 1H), 7.59-7.65 (m, 1H),7.17-7.42 (m, 5H), 7.09-7.12 (m, 1H), 6.91 (d, 1H), 6.77 (d, 1H), 3.81(t, 4H), 3.11 (t, 4H).

Example 37: Preparation of1-(4-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluorophenyl)3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(89.7 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 459.2, found 459.2. 1H NMR (DMSO-d₆, 300 MHz)δ 8.97 (s, 1H), 8.83 (s, 1H), 8.73 (s, 1H), 7.85 (d, 1H), 7.40-7.45 (m,3H), 7.36 (t, 1H), 7.17-7.21 (m, 2H), 7.06-7.21 (m, 2H), 6.91 (d, 1H),6.74 (d, 1H), 3.80 (t, 4H), 3.08 (t, 4H).

Example 38: Preparation of1-(3,5-difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-difluorophenyl)3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-Difluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(73.3 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H+) m/z calculated 477.2, found 477.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.32 (s, 1H), 9.23 (s, 1H), 8.71 (s, 1H), 7.85 (d, 1H), 7.35-7.42 (m,2H), 7.14-7.23 (m, 4H), 6.91 (d, 1H), 6.74-6.80 (m, 2H), 3.54-3.82 (m,4H), 2.89-2.96 (m, 4H).

Example 39: Preparation of1-(3-((3-(Piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(3-((3-(Piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(80.8 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H+) m/z calculated 509.2, found 509.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.17 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 7.97 (s, 1H), 7.85 (d, 1H),7.57 (d, 1H), 7.49 (t, 1H), 7.29-7.43 (m, 3H), 7.17-7.24 (m, 2H), 6.786(s, 1H), 6.77 (d, 1H), 3.57-3.78 (m, 4H), 2.45-2.51 (m, 4H).

Example 40: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(59.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H+) m/z calculated 543.1, found 543.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.36 (s, 1H), 9.21 (s, 1H), 8.70 (s, 1H), 8.07 (s, 1H), 7.84 (d, 1H),7.57-7.82 (m, 2H), 7.34-7.41 (m, 2H), 7.24 (d, 1H), 7.16 (d, 1H), 6.90(s, 1H), 6.78 (d, 1H), 3.58-3.74 (m, 4H), 2.88-2.94 (m, 4H).

Example 41: Preparation of1-(3-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl)3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(54.0 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.97-9.04 (m, 2H), 8.72 (s, 1H), 7.85 (d, 1H), 7.66 (s, 1H), 7.41 (s,1H), 7.36 (t, 1H), 7.17-7.30 (m, 4H), 7.01 (d, 1H), 6.91 (s, 1H), 6.77(d, 1H), 3.73-3.79 (m, 4H), 2.92-2.99 (m, 4H).

Example 42: Preparation of1-(4-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(67.8 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.15-9.21 (m, 2H), 8.75 (s, 1H), 7.87 (d, 1H), 7.46 (d, 3H), 7.34-7.42(m, 1H), 7.30 (d, 2H), 7.19-7.23 (m, 2H), 6.92 (s, 1H), 6.83 (d, 1H),4.08-4.10 (m, 4H), 3.06-3.08 (m, 4H).

Example 43: Preparation of1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea

1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea

1-(4-Fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea(60.1 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 477.2, found 477.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.01 (s, 2H), 8.72 (s, 1H), 7.86 (d, 1H), 7.55 (d, 1H), 7.35-7.45 (m,2H), 7.19-7.30 (m, 3H), 7.11 (d, 1H), 6.84 (d, 1H), 6.76 (t, 1H), 3.76(t, 4H), 2.94 (t, 4H).

Example 44: Preparation of1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea

1-(4-fluoro 3-((3-(piperazin 1 yl)quinoxalin 6 yl)oxy)phenyl) 3-(4fluorophenyl)urea

1-(4-Fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-fluorophenyl)urea(53.5 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 477.2, found 477.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.98 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 7.85 (d, 1H), 7.55 (d, 1H),7.34-7.44 (m, 3H), 7.20-7.26 (m, 2H), 7.09 (t, 2H), 6.84-6.85 (s, 1H),3.75 (t, 4H), 2.93 (t, 4H).

Example 45: Preparation of1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,4-Difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(83.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 495.2, found 495.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.18 (s, 2H), 8.75 (s, 1H), 7.88 (d, 1H), 7.55-7.65 (m, 2H), 7.23-7.40(m, 4H), 7.10 (d, 1H), 6.86 (d, 1H), 3.87 (t, 4H), 3.11 (t, 4H).

Example 46: Preparation of1-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3,5-Difluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(54.8 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 495.2, found 495.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.34 (s, 1H), 9.24 (s, 1H), 8.71 (s, 1H), 7.83-7.86 (d, 1H), 7.30-7.41(m, 1H), 7.12-7.29 (m, 5H), 6.73-6.84 (m, 2H), 3.73-3.76 (m, 4H),2.88-2.93 (m, 4H).

Example 47: Preparation of1-(3-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(81.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 493.2, found 493.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.21 (d, 2H), 8.74 (s, 1H), 7.88 (d, 1H), 7.67 (s, 1H), 7.57 (dd, 1H),7.39 (t, 1H), 7.23-7.30 (m, 4H), 6.99-7.01 (m, 1H), 6.86 (s, 1H), 3.85(s, 4H), 3.07-3.18 (m, 4H).

Example 48: Preparation of1-(4-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(54.2 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 493.2, found 493.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.96 (d, 2H), 8.72 (s, 1H), 7.85 (d, 1H), 7.54 (dd, 1H), 7.43 (d, 2H),7.34 (t, 1H), 7.19-7.28 (m, 4H), 6.85 (s, 1H), 3.73-3.77 (m, 4H),2.88-2.93 (m, 4H).

Example 49: Preparation of1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-Fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea(54.4 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 527.2, found 527.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.21 (d, 2H), 8.72 (s, 1H), 7.96 (s, 1H), 7.85 (d, 1H), 7.57 (d, 2H),7.48 (t, 1H), 7.38 (t, 1H), 7.20-7.31 (m, 3H), 6.84 (d, 1H), 3.73-3.80(m, 4H), 2.95-2.98 (m, 4H).

Example 50: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl) 3-(4fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(56.4 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 561.1, found 561.1. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.36 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 7.85 (d, 1H),7.52-7.65 (m, 3H), 7.27-7.41 (m, 2H), 7.19 (dd, 1H), 6.82 (s, 1H),3.68-3.73 (m, 4H), 2.84-2.90 (m, 4H).

Example 51: Preparation of1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chloro-4-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(55.6 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 511.1, found 511.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.07 (d, 2H), 8.72 (s, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.54 (d, 1H),7.20-7.40 (m, 5H), 6.84 (d, 1H), 3.72-3.77 (m, 4H), 2.93-2.95 (m, 4H).

Example 52: Preparation of1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-fluorophenyl)-3-(4-fluoro-3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(60.4 mg) was prepared as described for1-(3-fluorophenyl)-3-(3-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 511.1, found 511.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.10 (d, 2H), 8.73 (s, 1H), 7.86 (s, 1H), 7.63 (dd, 1H), 7.54 (dd,1H), 7.37-7.47 (m, 2H), 7.25-7.29 (m, 1H), 7.16-7.23 (m, 2H), 6.86 (d,1H), 3.73-3.75 (m, 4H), 2.89-2.92 (m, 4H).

Example 53: Preparation of3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide

3fluoro N (3-(quinoxalin-6-yloxy)phenyl)benzamide

To a solution of 3-fluorobenzoic acid (84 mg, 0.6 mmol, 1.2 eq) in DMF(10 mL) was added HATU (228 mg, 0.6 mmol, 1.2 eq) and DIEA (0.2 mL, 1mmol, 2 eq), followed by 3-(quinoxalin-6-yloxy)aniline (119 mg, 0.5mmol, 1 eq). The resulting mixture was stirred at room temperatureovernight, then concentrated. The resulting residue was dissolved in EA(50 mL), washed with aqueous Na₂CO₃ (30 mL) and HCl (1 N, 30 mL), driedby anhydrous Na₂SO₄ and concentrated. The resulting residue was purifiedby column chromatography (PE/EA=1:1, v/v) to afford3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide (70 mg, 39% yield).LCMS (M+H⁺) m/z calculated 360.1, found 360.1. ¹H NMR (CDCl₃, 400 MHz) δ8.75 (dd, 2H), 8.08 (d, 1H), 8.02 (s, 1H), 7.53-7.61 (m, 4H), 7.37-7.48(m, 4H), 7.22-7.25 (m, 1H), 6.93-6.96 (m, 1H).

Example 54: Preparation ofN-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide (31.8 mg)was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 410.1, found 410.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.76 (dd, 2H),8.08-8.11 (m, 2H), 8.04 (d, 1H), 7.98 (s, 1H), 7.80 (d, 1H), 7.58-7.64(m, 3H), 7.49 (d, 1H), 7.40-7.44 (m, 2H), 6.96-6.99 (m, 1H).

Example 55: Preparation of4-chloro-N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro N (3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(29.8 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 444.1, found 444.0. ¹H NMR (CDCl₃, 400 MHz) δ 8.74-8.76 (m,2H), 8.16 (d, 1H), 8.07-8.10 (m, 2H), 7.94-7.97 (m, 1H), 7.57-7.62 (m,3H), 7.46 (d, 1H), 7.38-7.44 (m, 2H), 6.96-6.99 (m, 1H).

Example 56: Preparation of4-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(36.7 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 460.1, found 460.0. ¹H NMR (CDCl₃, 400 MHz) δ 8.77 (s, 2H),8.10-8.16 (m, 2H), 7.92-7.97 (m, 2H), 7.70-7.72 (m, 1H), 7.62-7.65 (m,2H), 7.39-7.43 (m, 2H), 7.24-7.29 (t, 1H).

Example 57: Preparation of3-fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide

3-fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide

3-Fluoro-N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)benzamide (43.1 mg)was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 378.1, found 378.1. ¹H NMR (CDCl₃, 300 MHz) δ 8.78 (d, 2H),8.13 (d, 1H), 7.88 (s, 1H), 7.75 (dd, 1H), 7.39-7.67 (m, 6H), 7.29 (s,1H), 7.25 (t, 1H).

Example 58: Preparation ofN-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(56 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 428.1, found 428.1. ¹H NMR (CDCl₃, 300 MHz) δ 8.78 (s, 2H),8.03-8.14 (m, 4H), 7.73-7.83 (m, 2H), 7.63-7.67 (m, 2H), 7.40-7.46 (m,2H), 7.23-7.30 (m, 1H).

Example 59: Preparation of4-chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide(52.3 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 547.1, found 547.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.45 (s, 1H),8.15 (d, 1H), 7.95 (dd, 1H), 7.88 (d, 1H), 7.77 (s, 1H), 7.64 (d, 1H),7.53 (dd, 1H), 7.43-7.47 (m, 1H), 7.22-7.27 (m, 2H), 7.06 (d, 1H), 3.85(t, 4H), 3.73 (t, 4H).

Example 60: Preparation of3-fluoro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide

3-fluoro N (4 fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide

3-Fluoro-N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide(32.6 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 463.2, found 463.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.46 (s, 1H),7.88 (d, 1H), 7.80 (s, 1H), 7.44-7.58 (m, 5H), 7.25 (d, 1H), 7.23-7.24(m, 2H), 7.06 (d, 1H), 3.84 (t, 4H), 3.73 (t, 4H).

Example 61: Preparation ofN-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide(43.9 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 513.1, found 513.0. ¹H NMR (CDCl₃, 400 MHz) δ 8.45 (s, 1H),8.05 (t, 2H), 7.80-7.88 (m, 3H), 7.58 (t, 3H), 7.23 (dd, 2H), 7.06 (d,1H), 3.84 (t, 4H), 3.73 (t, 4H).

Example 62: Preparation ofN-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(42.8 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 428.1, found 428.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.76 (s, 2H),8.32 (s, 1H), 8.06-8.10 (m, 2H), 8.00 (d, 1H), 7.78 (d, 1H), 7.52-7.60(m, 3H), 7.37-7.41 (m, 1H), 7.22 (s, 1H), 6.64-6.68 (m, 1H).

Example 63: Preparation of4-chloro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro N (3fluoro5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(60.7 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 462.1, found 462.0. ¹H NMR (CDCl₃, 400 MHz) δ 8.82 (s, 1H),8.75 (s, 2H), 8.10 (d, 1H), 8.04 (d, 1H), 7.90-7.92 (m, 1H), 7.48-7.53(m, 3H), 7.33-7.36 (m, 1H), 7.19 (s, 1H), 6.62-6.66 (m, 1H).

Example 64: Preparation of3-fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide

3-fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide

3-Fluoro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)benzamide(27.6 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 463.2, found 463.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (s, 1H),7.90-7.93 (m, 1H), 7.83 (s, 1H), 7.56-7.63 (m, 2H), 7.43-7.53 (m, 2H),7.26-7.32 (m, 1H), 7.19-7.24 (m, 2H), 7.09 (s, 1H), 6.63-6.68 (m, 1H),3.86-3.90 (m, 4H), 3.76-3.81 (m, 4H).

Example 65: Preparation ofN-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide(41.1 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 513.1, found 513.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (d, 2H),7.98-8.05 (m, 2H), 7.75-7.83 (m, 2H), 7.54-7.59 (m, 1H), 7.39-7.44 (m,1H), 7.04-7.20 (m, 3H), 6.61-6.65 (m, 1H), 3.81-3.85 (m, 4H), 3.69-3.73(m, 4H).

Example 66: Preparation of4-chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(trifluoromethyl)benzamide(49.5 mg) was prepared as described for3-fluoro-N-(3-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS (M+H⁺) m/zcalculated 547.1, found 547.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.48 (s, 1H),8.14 (d, 1H), 7.93-7.96 (m, 1H), 7.85-7.89 (m, 2H), 7.64 (d, 1H),7.39-7.43 (m, 1H), 7.16-7.20 (m, 2H), 7.05 (s, 1H), 6.63-6.66 (m, 1H),3.84-3.87 (m, 4H), 3.73-3.76 (m, 4H).

Example 67: Preparation ofN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

To a solution of 3-(quinoxalin-6-yloxy)aniline (70 mg, 0.29 mmol) in DCM(20 mL) was added TEA (0.4 mL, 2.9 mmol), followed by propane-1-sulfonylchloride (0.17 mL, 1.48 mmol). The resulting mixture was stirred at roomtemperature for 1 h, then washed with water and extracted with DCM (20mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The resulting residue was purified by columnchromatography to affordN-(propylsulfonyl)-N-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide(94 mg, 72% yield).

To a solution ofN-(propylsulfonyl)-N-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide(94 mg, 0.21 mmol, 1 eq) in MeOH (10 mL) was added 1N NaOH (0.42 mL,0.56 mmol, 2 eq) and the resulting mixture was stirred at r.t for 10min, then concentrated. The resulting residue was purified by columnchromatography (PE/EA=1/1, v/v) to affordN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide (57 mg, 79%yield). LRMS (M+H⁺) m/z calculated 344.1, found 344.1. ¹H NMR (CDCl₃,400 MHz) δ 8.78 (d, 2H), 8.10 (d, 1H), 7.55-7.58 (m, 2H), 7.44 (d, 1H),7.34-7.38 (m, 1H), 7.07-7.09 (m, 2H), 6.91 (dd, 1H), 3.11-3.15 (m, 2H),1.83-1.89 (m, 2H), 1.03 (t, 3H).

Example 68: Preparation ofN-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(4-fluoro-3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide (21.7 mg)was prepared as described forN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide. LRMS (M+H⁺) m/zcalculated 362.1, found 362.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.78 (s, 2H),8.12 (d, 1H), 7.60-7.63 (m, 1H), 7.19-7.32 (m, 4H), 7.05-7.09 (m, 1H),3.09 (t, 2H), 1.83-1.88 (m, 2H), 1.03 (t, 3H).

Example 69: Preparation ofN-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide (42.5 mg)was prepared as described forN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide. LCMS (M+H⁺) m/zcalculated 362.1, found 362.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.79-8.81 (m,2H), 8.12 (d, 1H), 8.06 (s, 1H), 7.52-7.58 (m, 2H), 6.82-6.88 (m, 2H),6.57-6.61 (m, 1H), 3.14-3.18 (m, 2H), 1.83-1.89 (m, 2H), 1.02-1.06 (t,3H).

Example 70: Preparation ofN-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide

N-(4-fluoro3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide

N-(4-fluoro-3-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide(33.3 mg) was prepared as described forN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide. LRMS (M+H⁺) m/zcalculated 447.1, found 447.2. ¹H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H),7.87 (d, 1H), 7.18-7.23 (m, 2H), 6.99-7.08 (m, 3H), 6.30 (s, 1H), 3.85(t, 4H), 3.74 (t, 4H), 3.05-3.09 (m, 2H), 1.83-1.88 (m, 2H), 1.04 (t,3H).

Example 71: Preparation ofN-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide

N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide

N-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)propane-1-sulfonamide(30.9 mg) was prepared as described forN-(3-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide. LCMS (M+H⁺) m/zcalculated 447.1, found 447.2. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.19 (s,1H), 8.76 (s, 1H), 7.88 (d, 1H), 7.18-7.21 (m, 21H), 7.06 (d, 1H),6.82-6.85 (m, 1H), 6.71-6.74 (m, 2H), 3.73 (s, 8H), 3.14-3.19 (m, 2H),1.63-1.69 (m, 2H), 0.94 (t, 3H).

Example 72: Preparation of1-(3-fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea

1 (3fluoro 5-((3-morpholinoquinoxalin 6 yl)oxy)phenyl)3-(3fluorophenyl)urea

1-(3-Fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea(16.2 mg) was prepared as described for1-(3-Fluoro-5-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(3-fluorophenyl)urea.LCMS (M+H^(±)) m/z calculated 478.4, found 478.2. ¹H NMR (CD3OD, 400MHz) δ 8.43 (s, 1H), 7.70 (d, 1H), 7.24-7.28 (m, 1H), 7.10-7.16 (m, 1H),7.03-7.07 (m, 2H), 7.00 (d, 1H), 6.93-6.96 (m, 1H), 688 (d, 1H),6.59-6.64 (m, 1H), 6.36-6.40 (m, 1H), 3.62-3.70 (m, 8H).

Example 73: Preparation of3-fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide

3-fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide

3-Fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide (46.6 mg)was prepared as described for3-Fluoro-N-(3-fluoro-5-(quinoxalin-6-yloxy)phenyl)benzamide. LCMS(M+H^(±)) m/z calculated 378.3, found 378.1. ¹H NMR (CDCl₃, 400 MHz) δ8.76-8.78 (m, 2H), 8.17 (s, 1H), 8.09 (d, 1H), 7.50-7.58 (m, 4H),7.36-7.43 (m, 2H), 7.20-7.27 (m, 2H), 6.63-6.66 (m, 1H).

Example 74: Preparation of1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl) 3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

To a solution of quinoxalin-2(1H)-one (54.64 g, 374 mmol, 1.0 eq.) inHOAc (1000 mL) was added a solution of Br₂ (19.18 mL, 374 mmol, 1.0 eq.)in HOAc (200 mL) dropwise. The resulting mixture was stirred at roomtemperature for 12 h, then poured into ice-water. The precipitate wascollected by filtration and dried to afford 7-bromoquinoxalin-2(1H)-one(74 g, 88%).

To a suspension of 7-bromoquinoxalin-2(1H)-one (224 g, 1.0 mol, 1.0 eq.)in POCl₃ (1000 mL) was added DMF (3.65 g, 0.05 mol, 0.05 eq.). Theresulting mixture was stirred at 120° C. for 2 h, then cooled to roomtemperature and slowly poured into ice-water with vigorous stirring. Theprecipitate was collected by filtration and dried to afford7-bromo-2-chloroquinoxaline (180 g, 75%).

To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2 mol, 1.0 eq.) inCH₃CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K₂CO₃(85 g, 0.61 mol, 3.0 eq). The resulting mixture was stirred at 90° C.for 2 h, then cooled and filtered. The filtrate was concentrated and theresulting residue was re-crystallized from EA to afford4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3%).

To a solution of 4-(7-bromoquinoxalin-2-yl)morpholine (8.85 g, 30.0mmol, 1.0 eq.) and N-(4-hydroxyphenyl)pivalamide (6.95 g, 36.0 mmol, 1.2eq.) in DMF (200 mL) were added CuI (5.7 g, 30.0 mmol, 1.0 eq.) andCs₂CO₃ (19.5 g, 60.0 mmol, 2.0 eq.). The resulting mixture was stirredat 145° C. overnight, then cooled and concentrated. The resultingresidue was dissolved in EA (100 mL) and the resulting precipitate wasremoved by filtration. The filtrate was concentrated and the resultingresidue was purified by column chromatography (PE/EA=1:1 to EA, v/v) toafford N-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)pivalamide (2.9 g,23%).

To a solution ofN-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)pivalamide (2.9 g, 7.1mmol, 1.0 eq.) in HOAc (20 mL) was added conc. HCl (10 mL). The mixturewas stirred at 110° C. for 5 h, then cooled and poured onto ice (100mL). The mixture was adjusted to pH 10 by the addition of NaOH (1 N)solution, then extracted with DCM (100 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated. The resultingresidue was purified by column chromatography (PE/EA=1/4, v/v) to afford4-((3-morpholinoquinoxalin-6-yl)oxy)aniline (1.15 g, 50% yield).

To a solution of 4-((3-morpholinoquinoxalin-6-yl)oxy)aniline (50 mg,0.13 mmol, 1.0 eq.) in THF (5 mL) were added DIEA (0.05 mL, 1.2 eq.) and1-chloro-3-isocyanatobenzene (26 mg, 0.19 mmol, 1.5 eq.). The resultingmixture was stirred at room temperature for 1.5 h and concentrated. Theresulting residue was purified by column chromatography (PE/EA=1/1, v/v)to afford1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(61.9 mg, 84% yield). LRMS (M+H⁺) m/z calculated 476.1, found 476.2. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.94 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H),7.82-7.84 (d, 1H), 7.73 (s, 1H), 7.54 (d, 2H), 7.27-7.33 (m, 2H),7.11-7.18 (m, 3H), 7.01-7.03 (m, 1H), 6.79 (d, 1H), 3.70 (s, 8H).

Example 75: Preparation of1-(4-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Fluorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(65.5 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 460.2, found 460.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.74-8.76 (d, 2H), 8.68 (s, 1H), 7.81-7.84 (s, 1H), 7.45-7.55 (m, 4H),7.10-7.18 (m, 5H), 6.78 (s, 1H), 3.70-3.75 (s, 8H).

Example 76: Preparation of1-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-((3-Morpholinoquinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(64.8 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 510.2, found 510.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.15 (s, 1H), 8.91 (s, 1H), 8.69 (s, 1H), 7.82-7.85 (d, 1H), 7.62-7.69(m, 4H), 7.53-7.56 (m, 2H), 7.10-7.19 (m, 3H), 6.79-6.80 (s, 1H),3.64-3.75 (s, 8H).

Example 77: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(52.2 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 544.1, found 544.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.21 (s, 1H), 8.95 (s, 1H), 8.69 (s, 1H), 8.12-8.13 (s, 1H), 7.82-7.84(d, 1H), 7.60-7.68 (m, 2H), 7.52-7.56 (d, 2H), 7.11-7.19 (m, 3H),6.79-6.80 (d, 1H), 3.66-3.75 (s, 8H).

Example 78: Preparation of1-(4-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(44.7 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 476.1, found 476.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.83-8.85 (s, 1H), 8.80 (s, 1H), 8.69 (s, 1H), 7.82-7.84 (d, 1H),7.47-7.55 (m, 4H), 7.32-7.37 (m, 2H), 7.11-7.18 (m, 3H), 6.77-6.79 (d,1H), 3.62-3.63 (s, 8H).

Example 79:1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea(80.8 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 528.2, found 528.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.10 (s, 1H), 8.93 (s, 1H), 8.69 (s, 1H), 8.01-8.03 (m, 1H), 7.82-7.84(d, 1H), 7.64-7.68 (m, 1H), 7.54-7.56 (d, 2H), 7.42-7.47 (t, 1H),7.12-7.18 (m, 3H), 6.79-6.80 (s, 1H), 3.70-3.75 (s, 8H).

Example 80: Preparation of1-(3-fluorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea

1-(3-fluorophenyl) 3-(4 (quinoxalin-6-yloxy)phenyl)urea

1-(3-Fluorophenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea (30.3 mg) wasprepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 375.1, found 375.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 8.95 (s, 1H), 8.84-8.88 (m, 3H), 8.12 (d, 1H), 7.65 (dd, 1H),7.56-7.60 (m, 2H), 7.48-7.53 (m, 1H), 7.28-7.34 (m, 1H), 7.26 (d, 1H),7.17-7.21 (m, 2H), 7.13-7.15 (m, 1H), 6.76-6.81 (m, 1H).

Example 81: Preparation of1-(4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea

1-(4-(Quinoxalin-6-yloxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (33.0mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 425.1, found 425.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.09 (s, 1H), 8.92 (s, 1H), 8.84-8.88 (m, 2H), 8.13 (d, 1H), 8.02 (s,1H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 3H), 7.50-7.54 (m, 1H), 7.32 (d,1H), 7.26 (d, 1H), 7.18-7.21 (m, 2H).

Example 82: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-(quinoxalin-6-yloxy)phenyl)urea(31.9 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 459.1, found 459.0. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.20 (s, 1H), 8.97 (s, 1H), 8.84-8.88 (m, 2H), 8.11-8.14 (m, 2H),7.57-7.68 (m, 5H), 7.26 (d, 1H), 7.19 (d, 2H).

Example 83: Preparation of1-(3-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(3-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(3-Chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea (65.1mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LCMS (M+H⁺) m/z calculated 409.1, found 409.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.25 (s, 1H), 8.89 (dd, 2H), 8.65 (d, 1H), 8.13-8.18 (t, 2H),7.66-7.74 (m, 2H), 7.24-7.38 (m, 4H), 7.03-7.07 (m, 2H).

Example 84: Preparation of1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-fluorophenyl)urea

1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl) 3-(4-fluorophenyl)urea

1-(2-Fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-fluorophenyl)urea (95.2mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 393.1, found 393.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.09 (s, 1H), 8.88 (dd, 2H), 8.57 (d, 1H), 8.13-8.20 (m, 2H),7.66-7.69 (m, 1H), 7.46-7.49 (m, 2H), 7.36 (m, 1H), 7.27-7.31 (m, 2H),7.04-7.16 (m, 3H).

Example 85: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea(59.0 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 477.1, found 477.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.33 (br, 2H), 8.89 (dd, 2H), 8.09-8.16 (m, 3H), 7.63-7.70 (m, 3H),7.38 (ds, 1H), 7.29 (dd, 1H), 7.06 (dd, 3H).

Example 86: Preparation of1-(4-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chlorophenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea (34.7mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 409.1, found 409.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.19 (s, 1H), 8.87-8.91 (dd, 2H), 8.62 (s, 1H), 8.13-8.19 (m, 2H),7.66-7.69 (dd, 1H), 7.48-7.51 (m, 2H), 7.27-7.37 (m, 4H), 7.06 (d, 1H).

Example 87: Preparation of1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(2-Fluoro-4-(quinoxalin-6-yloxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(34.5 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M−H⁻) m/z calculated 448.1, found 448.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.47 (s, 1H), 8.87-8.91 (dd, 2H), 8.71 (ds, 1H), 8.13-8.19 (m, 2H),7.64-7.70 (m, 5H), 7.38 (ds, 1H), 7.28-7.32 (m, 1H), 7.05-7.08 (m, 3H).

Example 88: Preparation of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea(34.6 mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 461.1, found 461.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.39 (br, 2H), 8.87-8.91 (m, 2H), 8.67 (s, 1H), 8.10-8.16 (m, 2H),8.02-8.04 (m, 1H), 7.60-7.70 (m, 2H), 7.28-7.49 (m, 3H), 7.04-7.07 (m,1H).

Example 89: Preparation of1-(3-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(3-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(3-Chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea (57.6mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 409.1, found 409.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.12 (s, 1H), 9.04 (s, 1H), 8.88 (dd, 2H), 8.14 (d, 1H), 7.69-7.76 (m,2H), 7.26-7.41 (m, 4H), 7.22 (ds, 4H), 7.03-7.06 (m, 1H).

Example 90: Preparation of1-(4-chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-chlorophenyl) 3-(3fluoro-4-(quinoxalin-6-yloxy)phenyl)urea

1-(4-Chlorophenyl)-3-(3-fluoro-4-(quinoxalin-6-yloxy)phenyl)urea (67.3mg) was prepared as described for1-(3-chlorophenyl)-3-(4-((3-morpholinoquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 409.1, found 409.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.07 (s, 1H), 8.96 (s, 1H), 8.87 (dd, 2H), 8.15 (d, 1H), 7.69-7.76 (m,2H), 7.51 (d, 2H), 7.33-7.40 (m, 3H), 7.26 (dd, 1H), 7.21 (d, 1H).

Example 91: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea(27.6 mg) was prepared as described for1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-hydroxyquinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.8, found 475.1. ¹H NMR (DMSO-d₆, 400 MHz)δ 12.19 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H),7.76 (d, 1H), 7.54-7.65 (m, 4H), 7.12 (d, 2H), 6.95 (dd, 1H), 6.73 (d,1H).

Example 92: Preparation of1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

To a solution of 7-bromo-2-chloroquinoxaline (7.0 g, 29 mmol, 1.0 eq.)in CH₃CN (150 mL) were added tert-butyl piperazine-1-carboxylate (5.95g, 32 mmol, 1.1 eq.) and K₂CO₃ (12 g, 87 mol, 3.0 eq.). The resultingmixture was stirred at 100° C. for 2 h, then cooled and filtered. Thefiltrate was washed with 10% citric acid (50 mL×3), dried andconcentrated to affordtert-butyl-4-(7-bromoquinoxalin-2-yl)piperazine-1-carboxylate (11.3 g,99%) which was directly used in the next step without furtherpurification.

To a solution of tert-butyl4-(7-bromoquinoxalin-2-yl)piperazine-1-carboxylate (19.7 g, 50.0 mmol,1.0 eq.) and N-(4-hydroxyphenyl)pivalamide (14.4 g, 75.0 mmol, 1.5 eq.)in DMF (200 mL) were added CuI (9.5 g, 50.0 mmol, 1.0 eq.) and K₂CO₃(13.8 g, 100.0 mmol, 2.0 eq.). The resulting mixture was stirred at 145°C. overnight, then cooled to room temperature and concentrated. Theresulting residue was dissolved in EA (300 mL) and the resulting solidwas removed by filtration. The filtrate was concentrated and theresulting residue was purified by column chromatography (PE/EA=1:1 toEA, v/v) to afford tert-butyl4-(7-(4-pivalamidophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (5.1g, 25%).

To a solution of tert-butyl4-(7-(4-pivalamidophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (5.1g, 12.6 mmol, 1.0 eq.) in HOAc (40 mL) was added con. HCl (20 mL). Themixture was stirred at 110° C. for 5 h, then cooled and poured onto ice(100 mL). The resulting mixture was adjusted to pH=10 by the addition of1N NaOH solution, then extracted with DCM (100 mL×3). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated toafford 4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)aniline (1.8 g, 45%)which was directly used in the next step without further purification.

To a solution of 4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)aniline (1.8g, 5.6 mmol, 1.0 eq.) in THF (20 mL) were added (Boc)₂O (1.22 g, 5.6mmol, 1.0 eq.) and TEA (565 mg, 5.6 mmol, 1.0 eq.). The resultingmixture was stirred at room temperature for 0.5 h, then concentrated.The resulting residue was purified by column chromatography (PE/EA=1/1,v/v) to afford tert-butyl4-(7-(4-aminophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (0.9 g,39%).

To a solution of tert-butyl4-(7-(4-aminophenoxy)quinoxalin-2-yl)piperazine-1-carboxylate (105 mg,0.25 mmol, 1.0 eq.) in THF (5 mL) was added DIEA (0.5 mL, 2.5 mmol, 10.0eq.), followed by 1-fluoro-4-isocyanatobenzene (171 mg, 1.25 mmol, 5.0eq.). The resulting mixture was stirred at room temperature for 1.5 hand concentrated. The resulting residue was purified by columnchromatography (PE/EA=1/1, v/v) to afford tert-butyl tert-butyl4-(7-(4-(3-(4-fluorophenyl)ureido)phenoxy)quinoxalin-2-yl)piperazine-1-carboxylate(138 mg, ca. 100%).

To a solution of tert-butyl4-(7-(4-(3-(4-fluorophenyl)ureido)phenoxy)quinoxalin-2-yl)piperazine-1-carboxylate(138 mg, 0.25 mmol, 1.0 eq.) in DCM (3 mL) was added TFA (1 mL). Theresulting mixture was stirred at room temperature for 1 h, thenconcentrated. The resulting residue was basified to pH 7-8 by theaddition aqueous NaHCO₃ solution and extracted with DCM (20 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄ andconcentrated to afford1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(88.2 mg). LRMS (M+H⁺) m/z calculated 459.2, found 459.2. ¹H NMR(DMSO-d₆, 300 MHz) δ 8.82-8.84 (d, 2H), 8.66 (s, 1H), 7.78-7.80 (d, 1H),7.46-7.56 (m, 4H), 7.10-7.15 (m, 5H), 6.75-6.76 (d, 1H), 3.62-3.65 (t,4H), 2.76-2.79 (t, 4H).

Example 93: Preparation of1-(3-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(3-Chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(105 mg) was prepared as described for1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.05 (s, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 7.72-7.81 (m, 1H), 7.53-7.56(d, 2H), 7.29-7.31 (m, 2H), 7.10-7.14 (m, 4H), 6.75-6.76 (d, 1H),3.64-3.65 (t, 4H), 2.76-2.79 (t, 4H).

Example 94: Preparation of1-(4-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Chlorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(93.8 mg) was prepared as described for1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 475.2, found 475.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 8.86 (d, 2H), 8.66 (s, 1H), 7.78-7.81 (d, 1H), 7.48-7.55 (m, 4H),7.31-7.34 (d, 2H), 7.10-7.14 (m, 3H), 6.75-6.75 (d, 1H), 3.62-3.65 (t,4H), 2.76-2.79 (t, 4H).

Example 95: Preparation of1-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea

1-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)3-(4-(trifluoromethyl)phenyl)urea

1-(4-((3-(Piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)-3-(4-(trifluoromethyl)phenyl)urea(49.1 mg) was prepared as described for1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 509.2, found 509.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.15 (s, 1H), 8.91 (s, 1H), 8.67 (d, 1H), 7.80 (dd, 1H), 7.54-7.69 (m,6H), 7.11-7.15 (m, 3H), 6.76-6.77 (m, 1H), 3.65 (s, 4H), 2.80 (t, 4H).

Example 96: Preparation of1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(50 mg) was prepared as described for1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 527.2, found 527.2. ¹H NMR (DMSO-d₆, 400 MHz)δ 9.09 (s, 1H), 8.92 (s, 1H), 8.66 (s, 1H), 8.01-8.03 (m, 1H), 7.79-7.81(d, 1H), 7.64-7.68 (m, 1H), 7.55 (d, 2H), 7.45 (t, 1H), 7.11-7.14 (m,3H), 6.77 (s, 1H), 3.64 (t, 4H), 2.78 (t, 4H).

Example 97: Preparation of1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea(57.3 mg) was prepared as described for1-(4-fluorophenyl)-3-(4-((3-(piperazin-1-yl)quinoxalin-6-yl)oxy)phenyl)urea.LRMS (M+H⁺) m/z calculated 543.1, found 543.2. ¹H NMR (DMSO-d₆, 300 MHz)δ 9.23 (s, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 8.12-8.13 (d, 1H), 7.78-7.81(d, 1H), 7.53-7.65 (m, 4H), 7.11-7.14 (m, 3H), 6.76-6.77 (d, 1H),3.62-3.65 (t, 4H), 2.76-2.79 (t, 4H).

Example 98: Preparation of3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide

3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide

To a solution of 4-(quinoxalin-6-yloxy)aniline (90 mg, 0.38 mmol, 1.0eq.) and 3-fluorobenzoic acid (64 mg, 0.46 mmol, 1.2 eq.) in DMF (10 mL)was added HATU (217 mg, 0.57 mmol, 1.5 eq.) and DIEA (0.2 mL, 1.14 mmol,3.0 eq.). The mixture was stirred at room temperature for 70 h, thenconcentrated. The resulting residue was dissolved in EA (50 mL), washedwith aqueous Na₂CO₃ (30 mL) and 1N HCl (30 mL), dried by anhydrousNa2SO4 and concentrated. The resulting residue was purified by columnchromatography (PE/EA=2:1, v/v) to afford3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide (39.2 mg). LRMS(M+H⁺) m/z calculated 360.1, found 360.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.76(dd, 2H), 8.09 (d, 1H), 7.87 (s, 1H), 7.71 (d, 2H), 7.57-7.67 (m, 3H),7.43-7.50 (m, 2H), 7.55-7.58 (m, 2H), 7.26-7.28 (m, 1H), 7.18 (d, 2H).

Example 99: Preparation ofN-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide (34.7 mg)was prepared as described for3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 410.1, found 410.1. ¹H NMR (CDCl₃, 400 MHz) δ 8.76 (dd, 2H),8.08-8.15 (m, 3H), 7.98 (s, 1H), 7.83 (d, 1H), 7.72 (d, 2H), 7.66 (t,1H), 7.57-7.60 (dd, 1H), 7.45 (d, 1H), 7.19 (d, 2H).

Example 100: Preparation of4-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide

4-Chloro-N-(4-(quinoxalin-6-yloxy)phenyl)-3-(trifluoromethyl)benzamide(33.8 mg) was prepared as described for3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 444.1, found 444.0. ¹H NMR (CDCl₃, 400 MHz) δ 8.756 (dd, 2H),8.22 (d, 1H), 8.09 (d, 1H), 8.00-8.03 (m, 2H), 7.65-7.71 (m, 3H), 7.58(dd, 1H), 7.44 (d, 1H), 7.18 (d, 2H).

Example 101: Preparation ofN-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-5-(trifluoromethyl)nicotinamide

N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-5-(trifluoromethyl)nicotinamide

N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-5-(trifluoromethyl)nicotinamide(54.8 mg) was prepared as described for3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M+H⁺) m/zcalculated 427.1, found 427.2. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.72 (s,1H), 9.02 (d, 1H), 8.90-8.94 (dd, 2H), 8.39 (s, 1H), 8.17-8.22 (m, 2H),7.71-7.75 (m, 2H), 7.50 (ds, 1H), 7.32-7.36 (dd, 1H), 7.11-7.14 (dd,1H).

Example 102: Preparation ofN-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-2-(trifluoromethyl)isonicotinamide

N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-2-(trifluoromethyl)isonicotinamide

N-(2-fluoro-4-(quinoxalin-6-yloxy)phenyl)-2-(trifluoromethyl)isonicotinamide(54.8 mg) was prepared as described for3-fluoro-N-(4-(quinoxalin-6-yloxy)phenyl)benzamide. LRMS (M−H⁺) m/zcalculated 427.1, found 427.2. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.72 (s,1H), 9.02 (d, 1H), 8.92 (dd, 2H), 8.39 (s, 1H), 8.17-8.22 (m, 2H),7.71-7.75 (m, 2H), 7.50 (ds, 1H), 7.34 (dd, 1H), 7.13 (dd, 1H).

Example 103: Preparation ofN-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

N-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide

To a solution of 4-(quinoxalin-6-yloxy)aniline (70 mg, 0.29 mmol, 1.0eq.) in DCM (20 mL) was added TEA (0.4 mL, 2.9 mmol, 10.0 eq.), followedby propane-1-sulfonyl chloride (0.17 mL, 1.45 mmol, 5.0 eq.). Theresulting mixture was stirred at room temperature for 1 h, then washedwith water and extracted with DCM (20 mL×3). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The resulting residuewas purified by column chromatography (PE/EA=4/1, v/v) to affordN-(propylsulfonyl)-N-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide(89 mg, 68%).

To a solution ofN-(propylsulfonyl)-N-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide(125 mg, 0.28 mmol, 1.0 eq.) in MeOH (10 mL) was added 1N NaOH (0.56 mL,0.56 mmol, 2.0 eq.) aqueous solution. The resulting mixture was stirredat room temperature for 1 h., then concentrated. The resulting residuewas purified by column chromatography (PE/EA=1/1, v/v) to affordN-(4-(quinoxalin-6-yloxy)phenyl)propane-1-sulfonamide (50.0 mg, 52%).LRMS (M+H⁺) m/z calculated 344.1, found 344.0. ¹H NMR (CDCl₃, 400 MHz) δ8.78 (d, 2H), 8.11 (d, 1H), 7.59 (d, 1H), 7.41 (s, 1H), 7.27-7.33 (m,2H), 7.13-7.15 (m, 3H), 3.13 (t, 2H), 1.89-1.94 (m, 2H), 1.08 (t, 3H).

Example 104: Inhibitory Activity Against Kinases BRAF and BRAF V600E

Inhibitory activities Inhibitory activities of compounds against BRAF,and BRAF V600E were measured by Invitrogen using Z′-LYTE® Method asbriefly described in the following. 4× Test compounds are dissolved in1% DMSO. Kinase reaction mixture consists of 0.09-0.34 ng B-Raf (or0.002-0.006 ng BRAF V600E), 1× inactive MAP2K1 (MEK1)/inactive MAPK1(ERK2), and 2 μM Ser/Thr 03 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl2, 1 mM EGTA. ATP solutions are diluted to a 4×ATP workingconcentration in Kinase Buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mMMgCl2, 1 mM EGTA). Reaction started by 30-second shaking of mixtureconsisting of 2.5 μL 4× test compound, 2.5 μL 2× kinase reaction mixtureand 2.5 μL 4×ATP Solution on Bar-coded Corning, low volume NBS, black384-well plate (Corning Cat. #3676). Then the mixture was incubated for60-minute at room temperature for the kinase reaction, followed byaddition of 5 μL of a 1:1024 dilution of development reagent A and30-second plate shake. The mixture was then incubated for another60-minute at room temperature for development reaction. Fluorescence wasread by plate reader. IC₅₀ was calculated by plotting the concentrationof compound vs the percentage of inhibition in treated wells usingGraphPad Prism 5.

Table 2 and 3 show % inhibition at 1 μM of several compounds of theinvention against BRAF and BRAF V600E, respectively, using Z′-LYTE®method. The scale utilized in Tables 2 and 3 is as follows: +++ morethan 89% inhibition; ++ between 70% and 89% inhibition; and + less than70% inhibition.

TABLE 2 Biological activity of several illustrative compounds againstBRAF Inhibition Compounds +++ C036, C038, C039, C040, C041, C050, C051,C059, C060, C061, C062, C063, C064, C065, C067, C068, C070, C091, C092++ C002, C005, C043, C044, C047, C048, C049, C052, C087, C090, C093,C094 + C003, C006, C021, C028, C034, C054, C066, C073, C074, C075, C081,C082, C088, C089, C096

TABLE 3 Biological activity of several illustrative compounds againstBRAF V600E Inhibition Compounds +++ C001, C003, C005, C006, C015, C016,C018, C021, C023, C024, C028, C031, C034, C036, C037, C038, C039, C040,C041, C042, C043, C044, C046, C047, C048, C050, C051, C052, C053, C054,C055, C056, C057, C058, C059, C060, C061, C062, C063, C064, C065, C066,C067, C068, C070, C073, C075, C081, C082, C087, C088, C089, C090, C091,C092, C093, C094, C096 ++ C002, C004, C005, C010, C014, C017, C020,C022, C025, C026, C027, C029, C032, C033, C035, C045, C049, C074, C076,C078, C083, C084, C085, C086,, C097, C098, C101, C102 + C009, C011,C019, C071, C077, C079, C095, C099, C100

Table 4 shows IC₅₀ values of several compounds of the invention againstBRAF V600E using Z′-LYTE® method. The scale utilized in Table 4 is asfollows: +++ less than 100 nM; and ++ greater than 100 nM.

TABLE 4 IC₅₀ of several illustrative compounds against BRAF V600E IC50Compounds +++ C005, C069 ++ C001, C003, C009, C075

Example 105: Inhibitory Activity Against Kinase KDR

Inhibitory activities of compounds against KDR (VEGFR2) were alsomeasured by Invitrogen using Z′-LYTE® Method as described above with thefollowing modification. The 2× KDR (VEGFR2)/Tyr 01 mixture is preparedin 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. The final10 μL Kinase Reaction consists of 0.5-11.7 ng KDR (VEGFR2) and 2 μM Tyr01 in 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA. Afterthe 1 hour Kinase Reaction incubation, 5 μL of a 1:256 dilution ofDevelopment Reagent B is added. Table 4 shows % inhibition at 1 μM ofseveral compounds of the invention using Z′-LYTE® method. The scaleutilized in Table 5 is as follows: +++ more than 89% inhibition; ++between 70% and 89% inhibition; and + less than 70% inhibition.

TABLE 5 Biological activity of several illustrative compounds againstKDR Inhibition Compounds +++ C001, C003, C005, C009, C026, C036, C038,C040, C041, C043, C049, C050, C051, C060, C063, C064, C065, C066, C067,C070, C081, C084, C086, C087, C088, C089, C090, C091 ++ C002, C005,C006, C010, C011, C018, C021, C022, C024, C025, C027, C028, C029, C032,C033, C035, C037, C039, C042, C044, C046, C047, C048, C052, C053, C055,C056, C057, C058, C059, C061, C062, C068, C073, C075, C076, C082, C083,C092, C093, C095 + C004, C015, C023, C031, C034, C045, C054, C071, C098

Table 6 shows IC50 values of several compounds of the invention againstKDR using Z′-LYTE® method. The scale utilized in Table 5 is as follows:+++ less than 100 nM; and ++ greater than 100 nM

TABLE 6 IC₅₀ of several illustrative compounds against KDR IC50Compounds +++ C001, C003, C069 ++ C005, C009, C075

Example 106: Inhibition of Cancer Cell Growth by Compounds Using MTT orMTS Assay

Inhibition of cell growth by compounds was measured using MTT or MTSassay. Tumor cell lines were purchased from ATCC (American Type CultureCollection, Manassas, Va.). All cell lines were maintained in RPMI 1640(Hyclone) supplemented with 10% fetal bovine serum (FBS, Hyclone),glutamine (2 mM, Hyclone), and antibiotics (penicillin 100 U/mL andstreptomycin 50 μg/mL) at 37° C. in a humidified atmosphere of 5% CO₂ inair. Taxol (as a positive control, Sigma) and compounds were dissolvedin DMSO (Sigma), and the final concentration of DMSO in the medium was1%. Tumor cells were plated in 96-well plates at densities of about 2000(A375) or 4000 (A549 and Colo205) cells/well of a 96-well plate andallowed to adhere/grow for 24 h. They were then treated with variousconcentrations of drug and incubated for 72 h. For MTT method, mediumwas then removed by inverting and tapping the plates. 100 μL of MTT (0.5mg/ml) was added to each well followed by an incubated at 37° C. for 4h. MTT was then removed and 200 μL of DMSO was added to each well, andthe ODs at 570 nm were measured after a 5 second shaking cycle in a96-well spectrophotometer. For MTS method, 20 μL MTS (CellTiter 96Aqueous One Solution, Promega) was added to each well followed by anincubated at 37° C. for 2-4 h, solutions were then directly put in a96-well spectrophotometer, and the ODs at 490 nm were measured.

All concentrations of compounds were tested in triplicate and controlswere averaged over 4 wells. IC₅₀ was calculated by plotting theconcentration of compound vs the percentage of inhibition in treatedwells using GraphPad Prism 5. Data for representative compounds areshown below. Table 7 shows IC₅₀ values of several compounds of theinvention against A375 cells, Table 8 against A549 cells and Table 9against Colo205 cells. The scale utilized in Tables 7-9 is as follows:+++ less than 1000 nM; ++ between 1000 nM and 5000 nM; and + greaterthan 5000 nM. The scale utilized in Table 8 is as follows: +++ less than2000 nM; ++ between 2000 nM and 5000 nM; and + greater than 5000 nM.

TABLE 7 IC₅₀ of several illustrative compounds in A375 cells IC₅₀Compounds +++ C009, C011, C022, C033, C034, C035, C089, C101 ++ C001,C008, C018, C019, C021, C023, C024, C026, C027, C028, C029, C032, C046,C047, C048, C052, C053, C054, C066, C074, C075, C076, C077, C084, C086,C087, C088, C090, C091, C098 + C002, C003, C004, C005, C006, C007, C010,C012, C013, C014, C015, C016, C017, C020, C025, C030, C031, C070, C071,C072, C073, C078, C079, C080, C083, C092, C093, C094, C095, C096, C097,C099, C100

TABLE 8 IC₅₀ of several illustrative compounds in A549 cells IC₅₀Compounds +++ C001, C009, C011, C021, C022, C024, C033, C041, C066,C067, C068, C087, C089, C090 ++ C003, C008, C010, C020, C023, C026,C029, C032, C035, C040, C046, C048, C049, C050, C051, C058, C059, C060,C062, C063, C064, C065, C073, C074, C075, C084, C086, C088, C091, C092,C095 + C005, C006, C007, C012, C013, C014, C015, C016, C018, C025, C027,C028, C031, C034, C036, C037, C038, C039, C042, C043, C044, C045, C047,C054, C055, C056, C061, C070, C076, C077, C079, C080, C081, C093, C097,C098, C103

TABLE 9 IC₅₀ of several illustrative compounds in Colo205 cells IC₅₀Compounds +++ C089 ++ C001, C087 + C082

Example 107: Inhibition of Tumor Growth in Xenograft Model

Cells were implanted in BALB/c female nude mice and grown as tumorxenografts. When tumors achieved 120-200 mm³, mice were assigned intotreatment and control groups using randomized block design based upontheir tumor volumes. Each group contained 6 tumor-bearing mice. Tumorswere measured twice weekly in two dimensions using a caliper, and thetumor volume was calculated from two-dimensional measurements using theequation V=0.5×a×b² where a and b are the long and short diameters ofthe tumor, respectively. Relative tumor volume (RTV) was defined asTV_(t)/TV_(i), the ratio of the volume on a given day (TV_(t)) and thevolume at the start of treatment (TV_(i)). Relative tumor growth rate(T/C) was defined as RTV_(T)/RTV_(C), the ratio of relative tumor volumeof treatment group (RTV_(T)) and relative tumor volume of control group(RTV_(C)) on a given day. Inhibition of tumor growth in a Colo205 tumorxenograft model is shown below in Table 10 for a compound of Table 1.

TABLE 10 In vivo activity of an illustrative compound in Colo205 tumormodel Tumor Tumor Volume Volume Pre- Post- Dose treatment treatmentCompound (mg/kg) Schedule Route (mm³) (mm³) T/C Vehicle — qd × 14 i.g.232.88 954.79 — C087 30 qd × 14 i.p. 237.13 796.35 81% C089 30 qd × 14i.p. 233.30 768.94 79%

While some embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. For example, for claimconstruction purposes, it is not intended that the claims set forthhereinafter be construed in any way narrower than the literal languagethereof, and it is thus not intended that exemplary embodiments from thespecification be read into the claims. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations on the scope of the claims.

What is claimed is:
 1. A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃, R₅,R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, halo, hydroxy,azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionallysubstituted alkoxy, optionally substituted cycloalkyloxy, optionallysubstituted aryloxy, optionally substituted heteroaryloxy, optionallysubstituted heterocycloalkyloxy, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted alkenyl,optionally substituted aryloxy, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocycloalkyl,optionally substituted amino, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminocarbonyl,optionally substituted aminosulfonyl, optionally substitutedcarbamimidoyl, or optionally substituted alkynyl; R₄ is hydrogen, cyano,halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl,optionally substituted alkoxy, optionally substituted cycloalkyloxy,optionally substituted heteroaryloxy, optionally substitutedheterocycloalkyloxy, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, optionally substituted amino, optionallysubstituted acyl, optionally substituted alkoxycarbonyl, optionallysubstituted aminocarbonyl, optionally substituted aminosulfonyl,optionally substituted carbamimidoyl, or optionally substituted alkynyl;and R₉ is hydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; and R₁₁ ishydroxyl, formyl, optionally substituted alkoxy, optionally substitutedcycloalkyl, optionally substituted heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, —COR₁₂, —CO₂R₁₂,—CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or —SO₂NR₁₂R₁₃,where R₁₂ is optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, optionally substituted aryl, or optionally substitutedheteroaryl; and R₁₃ and R₁₄ are independently hydrogen, optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or R₁₂ and R₁₃ may be joined together with anyintervening atoms to form an optionally substituted heterocycloalkylring; or R₉ and R₁₁ may be joined together with any intervening atoms toform an optionally substituted heterocycloalkyl ring; wherein: eachsubstituted acyl is —C(O)-(substituted alkyl), —C(O)-(substitutedcycloalkyl), —C(O)-(substituted aryl), —C(O)-(substituted heteroaryl),or —C(O)-(substituted heterocycloalkyl); each substituted alkoxy is—O-(substituted alkyl); each substituted alkoxycarbonyl is—C(O)—O-(substituted alkyl); each substituted amino is —NHR^(d) or—NR^(d)R^(e); wherein each R^(d) is independently hydroxyl, formyl,unsubstituted or substituted alkoxy, unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedacyl, unsubstituted or substituted carbamimidoyl, unsubstituted orsubstituted aminocarbonyl, unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted alkoxycarbonyl, sulfinyl,and sulfonyl; and each R^(e) is independently chosen from unsubstitutedor substituted alkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, or unsubstituted or substituted heterocycloalkyl; eachsubstituted carbamimidoyl is —C(═NR^(e′))—NR^(f)R^(g); wherein eachR^(e′) is independently chosen from hydrogen, cyano, unsubstituted orsubstituted alkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, or unsubstituted or substituted heterocycloalkyl; each R^(f)and R^(g) are independently hydrogen unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, or unsubstituted orsubstituted heterocycloalkyl; wherein at least one of R^(e′), R^(f), andR^(g) is not hydrogen; and each substituted alkyl, substitutedcycloalkyl, substituted aryl, substituted heterocycloalkyl, andsubstituted heteroaryl is substituted with one or more groupsindependently selected from —R^(a), —OR^(b), —NH₂, —NHR^(d),—NR^(d)R^(e), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—NR^(b)C(NR^(c))NR^(b)R^(c), —NR^(b)C(NCN)NR^(b)R^(c), —NR^(c)SO₂R^(d),halo, cyano, azido, nitro, oxo (as a substituent for cycloalkyl orheterocycloalkyl), —COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b),—OCO₂R^(d), —OCONR^(b)R^(c), —OP(O)(OR^(b))OR^(c), —SR^(b), —SOR^(a),—SO₂R^(a), and —SO₂NR^(b)R^(c); each R^(a) is independentlyunsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedcycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstitutedor substituted aryl, or unsubstituted or substituted heteroaryl; eachR^(b) is independently hydrogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substituted aryl, orunsubstituted or substituted heteroaryl; each R^(c) is independentlyhydrogen or unsubstituted or substituted C₁-C₄ alkyl; or R^(b) and R^(c)and the nitrogen to which they are attached, form an unsubstituted orsubstituted heterocycloalkyl group; each R^(d) is independentlyhydroxyl, formyl, unsubstituted or substituted alkoxy, unsubstituted orsubstituted alkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted acyl, unsubstituted or substitutedcarbamimidoyl, unsubstituted or substituted aminocarbonyl, unsubstitutedor substituted aryl, unsubstituted or substituted heteroaryl,unsubstituted or substituted heterocycloalkyl, unsubstituted orsubstituted alkoxycarbonyl, sulfinyl, and sulfonyl; and each R^(e) isindependently chosen from unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, or unsubstituted orsubstituted heterocycloalkyl; wherein when any R^(a), R^(b), R^(c),R^(d), R^(e), R^(e′), R^(f), or R^(g) group is substituted, the R^(a),R^(b), R^(c), R^(d), R^(e), R^(e′), R^(f), or R^(g) group is substitutedwith one or more substituents independently selected from a group Dconsisting of C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄ alkyl-,heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl, —OC₁-C₄ alkyl, —OC₁-C₄alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo, —OH, —NH₂, —C₁-C₄alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl), cyano, nitro, oxo (asa substituent for cycloalkyl or heterocycloalkyl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ alkylphenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).
 2. The compound or pharmaceutically acceptable salt of claim1, wherein R₁ is hydrogen, cyano, optionally substituted alkoxy,optionally substituted cycloalkyloxy, optionally substituted aryloxy,optionally substituted amino, optionally substituted alkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl.
 3. The compound or pharmaceutically acceptablesalt of claim 2, wherein R₁ is optionally substituted aryl, optionallysubstituted heterocycloalkyl, or optionally substituted heteroaryl. 4.The compound or pharmaceutically acceptable salt of claim 1, wherein R₂,R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionallysubstituted alkoxy, or optionally substituted alkyl.
 5. The compound orpharmaceutically acceptable salt of claim 4, wherein R₂, R₃, R₄, and R₅are independently hydrogen or halo.
 6. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R₆, R₇, R₈, and R₁₀ areindependently hydrogen, cyano, halo, optionally substituted alkoxy,optionally substituted alkyl, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted aminocarbonyl, oroptionally substituted aminosulfonyl.
 7. The compound orpharmaceutically acceptable salt of claim 6 wherein R₆, R₇, R₈, and R₁₀are independently hydrogen, cyano, or halo.
 8. The compound orpharmaceutically acceptable salt of claim 1, wherein R₉ is hydrogen,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted heterocycloalkyl, optionally substituted aryl, oroptionally substituted heteroaryl.
 9. The compound or pharmaceuticallyacceptable salt of claim 8, wherein R₉ is hydrogen or optionallysubstituted lower alkyl.
 10. The compound or pharmaceutically acceptablesalt of claim 9, wherein R₉ is hydrogen.
 11. The compound orpharmaceutically acceptable salt of claim 1, wherein R₁₁ is —COR₁₂,—CO₂R₁₂, —CONR₁₂R₁₃, —C(NR₁₄)NR₁₂R₁₃, —C(NCN)NR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃.
 12. The compound or pharmaceutically acceptable salt ofclaim 11, wherein R₁₁ is —COR₁₂, —CO₂R₁₂, —CONR₁₂R₁₃, —SO₂NR₁₂, or—SO₂NR₁₂R₁₃.
 13. The compound or pharmaceutically acceptable salt ofclaim 11, wherein R₁₂ is optionally substituted cycloalkyl, optionallysubstituted heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and R₁₃ and R₁₄ are independently hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl, oroptionally substituted heterocycloalkyl.
 14. The compound orpharmaceutically acceptable salt of claim 11, wherein R₁₂ and R₁₃ arejoined together with any intervening atoms to form an optionallysubstituted 4- to 8-membered heterocycloalkyl ring.
 15. The compound orpharmaceutically acceptable salt of claim 1, wherein R₉ and R₁₁ arejoined together with any intervening atoms to form an optionallysubstituted 4- to 8-membered heterocycloalkyl ring.
 16. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and thecompound or pharmaceutically acceptable salt of claim
 1. 17. Thepharmaceutical composition of claim 16, wherein the composition isformulated in a form chosen from the group consisting of tablets,capsules, powders, liquids, suspensions, suppositories, and aerosols.18. A method of treating a cancer mediated by BRAF in a subjectsuffering from the cancer, the method comprising administering to thesubject in need thereof a therapeutically effective amount of thecompound or pharmaceutically acceptable salt of claim
 1. 19. The methodof claim 18, wherein the cancer is melanoma, non-small cell lung cancer,colon cancer, thyroid cancer, or ovarian cancer.
 20. A method oftreating a disorder mediated by Raf in a subject suffering from thedisorder, comprising administering to the subject a therapeuticallyeffective amount of the compound or pharmaceutically acceptable salt ofclaim
 1. 21. A method of treating a disorder mediated by Raf in asubject suffering from the disorder, comprising: a. determining thepresence or absence of a BRAF mutation in a biological sample isolatedfrom the subject; and b. if a BRAF mutation is determined to be presentin the subject, administering to the subject a therapeutically effectiveamount of a compound or pharmaceutically acceptable salt of claim 1.